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  • Molecular Sequence Data  (52)
  • Crystallography, X-Ray
  • Signal Transduction
  • American Association for the Advancement of Science (AAAS)  (99)
  • American Meteorological Society
  • PANGAEA
  • 2015-2019  (99)
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  • 1995-1999
  • 2015  (99)
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  • 2015-2019  (99)
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  • 1
    Publication Date: 2015-05-23
    Description: Sex determination in the mosquito Aedes aegypti is governed by a dominant male-determining factor (M factor) located within a Y chromosome-like region called the M locus. Here, we show that an M-locus gene, Nix, functions as an M factor in A. aegypti. Nix exhibits persistent M linkage and early embryonic expression, two characteristics required of an M factor. Nix knockout with clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 resulted in largely feminized genetic males and the production of female isoforms of two key regulators of sexual differentiation: doublesex and fruitless. Ectopic expression of Nix resulted in genetic females with nearly complete male genitalia. Thus, Nix is both required and sufficient to initiate male development. This study provides a foundation for mosquito control strategies that convert female mosquitoes into harmless males.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hall, Andrew Brantley -- Basu, Sanjay -- Jiang, Xiaofang -- Qi, Yumin -- Timoshevskiy, Vladimir A -- Biedler, James K -- Sharakhova, Maria V -- Elahi, Rubayet -- Anderson, Michelle A E -- Chen, Xiao-Guang -- Sharakhov, Igor V -- Adelman, Zach N -- Tu, Zhijian -- AI113643/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 12;348(6240):1268-70. doi: 10.1126/science.aaa2850. Epub 2015 May 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Interdisciplinary PhD Program in Genetics, Bioinformatics, and Computational Biology, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, VA, USA. Department of Biochemistry, Virginia Tech, Blacksburg, VA, USA. Fralin Life Science Institute, Virginia Tech, Blacksburg, VA, USA. ; Fralin Life Science Institute, Virginia Tech, Blacksburg, VA, USA. Department of Entomology, Virginia Tech, Blacksburg, VA, USA. ; Department of Biochemistry, Virginia Tech, Blacksburg, VA, USA. Fralin Life Science Institute, Virginia Tech, Blacksburg, VA, USA. ; Department of Biochemistry, Virginia Tech, Blacksburg, VA, USA. ; School of Public Health and Tropical Medicine, Southern Medical University, Guangdong, People's Republic of China. ; Interdisciplinary PhD Program in Genetics, Bioinformatics, and Computational Biology, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, VA, USA. Fralin Life Science Institute, Virginia Tech, Blacksburg, VA, USA. Department of Entomology, Virginia Tech, Blacksburg, VA, USA. ; Interdisciplinary PhD Program in Genetics, Bioinformatics, and Computational Biology, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, VA, USA. Fralin Life Science Institute, Virginia Tech, Blacksburg, VA, USA. Department of Entomology, Virginia Tech, Blacksburg, VA, USA. jaketu@vt.edu zachadel@vt.edu. ; Interdisciplinary PhD Program in Genetics, Bioinformatics, and Computational Biology, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, VA, USA. Department of Biochemistry, Virginia Tech, Blacksburg, VA, USA. Fralin Life Science Institute, Virginia Tech, Blacksburg, VA, USA. jaketu@vt.edu zachadel@vt.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25999371" target="_blank"〉PubMed〈/a〉
    Keywords: Aedes/*genetics/*growth & development ; Animals ; Caspase 9 ; Clustered Regularly Interspaced Short Palindromic Repeats ; Female ; Gene Knockout Techniques ; *Genes, Insect ; *Genetic Loci ; Male ; Molecular Sequence Data ; Mosquito Control/methods ; Sex Determination Processes/*genetics
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  • 2
    Publication Date: 2015-07-15
    Description: Insulin-induced gene 1 (Insig-1) and Insig-2 are endoplasmic reticulum membrane-embedded sterol sensors that regulate the cellular accumulation of sterols. Despite their physiological importance, the structural information on Insigs remains limited. Here we report the high-resolution structures of MvINS, an Insig homolog from Mycobacterium vanbaalenii. MvINS exists as a homotrimer. Each protomer comprises six transmembrane segments (TMs), with TM3 and TM4 contributing to homotrimerization. The six TMs enclose a V-shaped cavity that can accommodate a diacylglycerol molecule. A homology-based structural model of human Insig-2, together with biochemical characterizations, suggest that the central cavity of Insig-2 accommodates 25-hydroxycholesterol, whereas TM3 and TM4 engage in Scap binding. These analyses provide an important framework for further functional and mechanistic understanding of Insig proteins and the sterol regulatory element-binding protein pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704858/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704858/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ren, Ruobing -- Zhou, Xinhui -- He, Yuan -- Ke, Meng -- Wu, Jianping -- Liu, Xiaohui -- Yan, Chuangye -- Wu, Yixuan -- Gong, Xin -- Lei, Xiaoguang -- Yan, S Frank -- Radhakrishnan, Arun -- Yan, Nieng -- HL-20948/HL/NHLBI NIH HHS/ -- P01 HL020948/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Jul 10;349(6244):187-91. doi: 10.1126/science.aab1091.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China. Center for Structural Biology, School of Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China. ; National Institute of Biological Sciences, Beijing 102206, China. ; Molecular Design and Chemical Biology, Therapeutic Modalities, Roche Pharma Research and Early Development, Roche Innovation Center Shanghai, Shanghai 201203, China. ; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26160948" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry ; Crystallography, X-Ray ; Diglycerides/chemistry ; Humans ; Hydroxycholesterols/chemistry/*metabolism ; Intracellular Signaling Peptides and Proteins/*chemistry ; Membrane Proteins/*chemistry ; Mycobacterium/*metabolism ; Protein Multimerization ; Protein Structure, Secondary ; Sterol Regulatory Element Binding Proteins/*chemistry
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  • 3
    Publication Date: 2015-04-11
    Description: Protein phosphorylation regulates virtually all biological processes. Although protein kinases are popular drug targets, targeting protein phosphatases remains a challenge. Here, we describe Sephin1 (selective inhibitor of a holophosphatase), a small molecule that safely and selectively inhibited a regulatory subunit of protein phosphatase 1 in vivo. Sephin1 selectively bound and inhibited the stress-induced PPP1R15A, but not the related and constitutive PPP1R15B, to prolong the benefit of an adaptive phospho-signaling pathway, protecting cells from otherwise lethal protein misfolding stress. In vivo, Sephin1 safely prevented the motor, morphological, and molecular defects of two otherwise unrelated protein-misfolding diseases in mice, Charcot-Marie-Tooth 1B, and amyotrophic lateral sclerosis. Thus, regulatory subunits of phosphatases are drug targets, a property exploited here to safely prevent two protein misfolding diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490275/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490275/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Das, Indrajit -- Krzyzosiak, Agnieszka -- Schneider, Kim -- Wrabetz, Lawrence -- D'Antonio, Maurizio -- Barry, Nicholas -- Sigurdardottir, Anna -- Bertolotti, Anne -- 309516/European Research Council/International -- MC_U105185860/Medical Research Council/United Kingdom -- R01-NS55256/NS/NINDS NIH HHS/ -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Apr 10;348(6231):239-42. doi: 10.1126/science.aaa4484.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK. ; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy. ; Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK. aberto@mrc-lmb.cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25859045" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; Cells, Cultured ; Charcot-Marie-Tooth Disease/drug therapy/metabolism/pathology ; Disease Models, Animal ; Endoplasmic Reticulum Stress/drug effects ; Enzyme Inhibitors/metabolism/pharmacokinetics/*pharmacology/toxicity ; Guanabenz/*analogs & derivatives/chemical ; synthesis/metabolism/pharmacology/toxicity ; HeLa Cells ; Humans ; Mice ; Mice, Transgenic ; Molecular Targeted Therapy ; Phosphorylation ; Protein Folding ; Protein Phosphatase 1/*antagonists & inhibitors ; Proteostasis Deficiencies/*drug therapy/*prevention & control ; Signal Transduction
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  • 4
    Publication Date: 2015-08-22
    Description: Plasma membrane depolarization can trigger cell proliferation, but how membrane potential influences mitogenic signaling is uncertain. Here, we show that plasma membrane depolarization induces nanoscale reorganization of phosphatidylserine and phosphatidylinositol 4,5-bisphosphate but not other anionic phospholipids. K-Ras, which is targeted to the plasma membrane by electrostatic interactions with phosphatidylserine, in turn undergoes enhanced nanoclustering. Depolarization-induced changes in phosphatidylserine and K-Ras plasma membrane organization occur in fibroblasts, excitable neuroblastoma cells, and Drosophila neurons in vivo and robustly amplify K-Ras-dependent mitogen-activated protein kinase (MAPK) signaling. Conversely, plasma membrane repolarization disrupts K-Ras nanoclustering and inhibits MAPK signaling. By responding to voltage-induced changes in phosphatidylserine spatiotemporal dynamics, K-Ras nanoclusters set up the plasma membrane as a biological field-effect transistor, allowing membrane potential to control the gain in mitogenic signaling circuits.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687752/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687752/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Yong -- Wong, Ching-On -- Cho, Kwang-jin -- van der Hoeven, Dharini -- Liang, Hong -- Thakur, Dhananiay P -- Luo, Jialie -- Babic, Milos -- Zinsmaier, Konrad E -- Zhu, Michael X -- Hu, Hongzhen -- Venkatachalam, Kartik -- Hancock, John F -- R01 NS081301/NS/NINDS NIH HHS/ -- R01NS081301/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2015 Aug 21;349(6250):873-6. doi: 10.1126/science.aaa5619.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Biology and Pharmacology, Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. ; Department of Diagnostic and Biomedical Sciences, Dental School, University of Texas Health Science Center at Houston, Houston, TX 77054, USA. ; Department of Neuroscience, University of Arizona, Tucson, AZ 85721, USA. ; Department of Integrative Biology and Pharmacology, Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Program in Cell and Regulatory Biology, University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA. ; Department of Integrative Biology and Pharmacology, Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Program in Cell and Regulatory Biology, University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA. john.f.hancock@uth.tmc.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26293964" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Cell Membrane/metabolism/*physiology ; Cricetinae ; Drosophila melanogaster ; Fibroblasts ; *Membrane Potentials ; Mice ; Neurons ; Phosphatidylinositol 4,5-Diphosphate/*metabolism ; Phosphatidylserines/*metabolism ; Signal Transduction ; ras Proteins/*metabolism
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  • 5
    Publication Date: 2015-01-03
    Description: Proton-pumping complex I of the mitochondrial respiratory chain is among the largest and most complicated membrane protein complexes. The enzyme contributes substantially to oxidative energy conversion in eukaryotic cells. Its malfunctions are implicated in many hereditary and degenerative disorders. We report the x-ray structure of mitochondrial complex I at a resolution of 3.6 to 3.9 angstroms, describing in detail the central subunits that execute the bioenergetic function. A continuous axis of basic and acidic residues running centrally through the membrane arm connects the ubiquinone reduction site in the hydrophilic arm to four putative proton-pumping units. The binding position for a substrate analogous inhibitor and blockage of the predicted ubiquinone binding site provide a model for the "deactive" form of the enzyme. The proposed transition into the active form is based on a concerted structural rearrangement at the ubiquinone reduction site, providing support for a two-state stabilization-change mechanism of proton pumping.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zickermann, Volker -- Wirth, Christophe -- Nasiri, Hamid -- Siegmund, Karin -- Schwalbe, Harald -- Hunte, Carola -- Brandt, Ulrich -- New York, N.Y. -- Science. 2015 Jan 2;347(6217):44-9. doi: 10.1126/science.1259859.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Bioenergetics Group, Institute of Biochemistry II, Medical School, Goethe-University, 60438 Frankfurt am Main, Germany. Cluster of Excellence Frankfurt "Macromolecular Complexes," Goethe-University, 60438 Frankfurt am Main, Germany. zickermann@med.uni-frankfurt.de carola.hunte@biochemie.uni-freiburg.de ulrich.brandt@radboudumc.nl. ; Institute for Biochemistry and Molecular Biology, ZBMZ, BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany. ; Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK. Institute of Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, 60438 Frankfurt am Main, Germany. ; Structural Bioenergetics Group, Institute of Biochemistry II, Medical School, Goethe-University, 60438 Frankfurt am Main, Germany. ; Cluster of Excellence Frankfurt "Macromolecular Complexes," Goethe-University, 60438 Frankfurt am Main, Germany. Institute of Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, 60438 Frankfurt am Main, Germany. ; Institute for Biochemistry and Molecular Biology, ZBMZ, BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany. zickermann@med.uni-frankfurt.de carola.hunte@biochemie.uni-freiburg.de ulrich.brandt@radboudumc.nl. ; Cluster of Excellence Frankfurt "Macromolecular Complexes," Goethe-University, 60438 Frankfurt am Main, Germany. Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. zickermann@med.uni-frankfurt.de carola.hunte@biochemie.uni-freiburg.de ulrich.brandt@radboudumc.nl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25554780" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; Electron Transport Complex I/*chemistry/ultrastructure ; Mitochondria/*enzymology ; Mitochondrial Membranes/*enzymology ; Protein Structure, Secondary ; Protons ; Ubiquinone/chemistry ; Yarrowia/enzymology
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  • 6
    Publication Date: 2015-07-04
    Description: Lactic acid racemization is involved in lactate metabolism and cell wall assembly of many microorganisms. Lactate racemase (Lar) requires nickel, but the nickel-binding site and the role of three accessory proteins required for its activation remain enigmatic. We combined mass spectrometry and x-ray crystallography to show that Lar from Lactobacillus plantarum possesses an organometallic nickel-containing prosthetic group. A nicotinic acid mononucleotide derivative is tethered to Lys(184) and forms a tridentate pincer complex that coordinates nickel through one metal-carbon and two metal-sulfur bonds, with His(200) as another ligand. Although similar complexes have been previously synthesized, there was no prior evidence for the existence of pincer cofactors in enzymes. The wide distribution of the accessory proteins without Lar suggests that it may play a role in other enzymes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Desguin, Benoit -- Zhang, Tuo -- Soumillion, Patrice -- Hols, Pascal -- Hu, Jian -- Hausinger, Robert P -- New York, N.Y. -- Science. 2015 Jul 3;349(6243):66-9. doi: 10.1126/science.aab2272.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA. ; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. ; Institute of Life Sciences, Universite Catholique de Louvain, B-1348 Louvain-la-Neuve, Belgium. ; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA. hujian1@msu.edu hausinge@msu.edu. ; Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA. Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. hujian1@msu.edu hausinge@msu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26138974" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/genetics ; Binding Sites ; Carbon/chemistry ; Catalysis ; Crystallography, X-Ray ; Histidine/chemistry ; Holoenzymes/chemistry ; Lactic Acid/*biosynthesis/chemistry ; Lactobacillus plantarum/*enzymology/genetics ; Ligands ; Lysine/chemistry ; Metalloproteins/*chemistry/genetics ; Niacin/*chemistry ; Nickel/*chemistry ; Nicotinamide Mononucleotide/analogs & derivatives/chemistry ; Protein Processing, Post-Translational ; Protein Structure, Secondary ; Racemases and Epimerases/*chemistry/genetics ; Spectrometry, Mass, Electrospray Ionization ; Sulfur
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  • 7
    Publication Date: 2015-05-23
    Description: Extremophiles, microorganisms thriving in extreme environmental conditions, must have proteins and nucleic acids that are stable at extremes of temperature and pH. The nonenveloped, rod-shaped virus SIRV2 (Sulfolobus islandicus rod-shaped virus 2) infects the hyperthermophilic acidophile Sulfolobus islandicus, which lives at 80 degrees C and pH 3. We have used cryo-electron microscopy to generate a three-dimensional reconstruction of the SIRV2 virion at ~4 angstrom resolution, which revealed a previously unknown form of virion organization. Although almost half of the capsid protein is unstructured in solution, this unstructured region folds in the virion into a single extended alpha helix that wraps around the DNA. The DNA is entirely in the A-form, which suggests a common mechanism with bacterial spores for protecting DNA in the most adverse environments.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DiMaio, Frank -- Yu, Xiong -- Rensen, Elena -- Krupovic, Mart -- Prangishvili, David -- Egelman, Edward H -- GM035269/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 May 22;348(6237):914-7. doi: 10.1126/science.aaa4181.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. ; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA. ; Institut Pasteur, Department of Microbiology, 25 rue du Dr. Roux, Paris 75015, France. ; Institut Pasteur, Department of Microbiology, 25 rue du Dr. Roux, Paris 75015, France. egelman@virginia.edu david.prangishvili@pasteur.fr. ; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA. egelman@virginia.edu david.prangishvili@pasteur.fr.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25999507" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cryoelectron Microscopy ; DNA, A-Form/*metabolism ; Molecular Sequence Data ; Protein Multimerization ; Protein Structure, Secondary ; Rudiviridae/*metabolism/ultrastructure ; Spores, Bacterial/genetics/virology ; Sulfolobus/*genetics/*virology ; Virion/*ultrastructure
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  • 8
    Publication Date: 2015-10-10
    Description: Strigolactones are naturally occurring signaling molecules that affect plant development, fungi-plant interactions, and parasitic plant infestations. We characterized the function of 11 strigolactone receptors from the parasitic plant Striga hermonthica using chemical and structural biology. We found a clade of polyspecific receptors, including one that is sensitive to picomolar concentrations of strigolactone. A crystal structure of a highly sensitive strigolactone receptor from Striga revealed a larger binding pocket than that of the Arabidopsis receptor, which could explain the increased range of strigolactone sensitivity. Thus, the sensitivity of Striga to strigolactones from host plants is driven by receptor sensitivity. By expressing strigolactone receptors in Arabidopsis, we developed a bioassay that can be used to identify chemicals and crops with altered strigolactone levels.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Toh, Shigeo -- Holbrook-Smith, Duncan -- Stogios, Peter J -- Onopriyenko, Olena -- Lumba, Shelley -- Tsuchiya, Yuichiro -- Savchenko, Alexei -- McCourt, Peter -- New York, N.Y. -- Science. 2015 Oct 9;350(6257):203-7. doi: 10.1126/science.aac9476.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell and Systems Biology, University of Toronto, 25 Willcocks Street, Toronto M5S 3B2, Canada. ; Department of Chemical Engineering and Applied Chemistry, Banting and Best Department of Medical Research, University of Toronto, 200 College Street, Toronto M5S 3E5, Canada. Center for Structural Genomics of Infectious Diseases, contracted by National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. ; Department of Chemical Engineering and Applied Chemistry, Banting and Best Department of Medical Research, University of Toronto, 200 College Street, Toronto M5S 3E5, Canada. ; Institute of Transformative Bio-Molecules, Nagoya University, Japan, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan. ; Cell and Systems Biology, University of Toronto, 25 Willcocks Street, Toronto M5S 3B2, Canada. peter.mccourt@utoronto.ca.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26450211" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arabidopsis/genetics/metabolism ; Catalytic Domain ; Germination/drug effects ; Heterocyclic Compounds, 3-Ring/*metabolism/pharmacology ; Lactones/*metabolism/pharmacology ; Molecular Sequence Data ; Phylogeny ; Plant Growth Regulators/*metabolism/pharmacology ; Plant Proteins/*chemistry/classification/genetics ; Protein Structure, Secondary ; Receptors, Cell Surface/*chemistry/classification/genetics ; Seeds/genetics/growth & development/metabolism ; Striga/genetics/growth & development/*metabolism ; Structure-Activity Relationship
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  • 9
    Publication Date: 2015-03-15
    Description: TREK-2 (KCNK10/K2P10), a two-pore domain potassium (K2P) channel, is gated by multiple stimuli such as stretch, fatty acids, and pH and by several drugs. However, the mechanisms that control channel gating are unclear. Here we present crystal structures of the human TREK-2 channel (up to 3.4 angstrom resolution) in two conformations and in complex with norfluoxetine, the active metabolite of fluoxetine (Prozac) and a state-dependent blocker of TREK channels. Norfluoxetine binds within intramembrane fenestrations found in only one of these two conformations. Channel activation by arachidonic acid and mechanical stretch involves conversion between these states through movement of the pore-lining helices. These results provide an explanation for TREK channel mechanosensitivity, regulation by diverse stimuli, and possible off-target effects of the serotonin reuptake inhibitor Prozac.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dong, Yin Yao -- Pike, Ashley C W -- Mackenzie, Alexandra -- McClenaghan, Conor -- Aryal, Prafulla -- Dong, Liang -- Quigley, Andrew -- Grieben, Mariana -- Goubin, Solenne -- Mukhopadhyay, Shubhashish -- Ruda, Gian Filippo -- Clausen, Michael V -- Cao, Lishuang -- Brennan, Paul E -- Burgess-Brown, Nicola A -- Sansom, Mark S P -- Tucker, Stephen J -- Carpenter, Elisabeth P -- 084655/Wellcome Trust/United Kingdom -- 092809/Z/10/Z/Wellcome Trust/United Kingdom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Mar 13;347(6227):1256-9. doi: 10.1126/science.1261512.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. ; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. ; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. ; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK. ; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK. ; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. ; Pfizer Neusentis, Granta Park, Cambridge CB21 6GS, UK. ; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK. ; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. liz.carpenter@sgc.ox.ac.uk stephen.tucker@physics.ox.ac.uk. ; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. liz.carpenter@sgc.ox.ac.uk stephen.tucker@physics.ox.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25766236" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arachidonic Acid/pharmacology ; Binding Sites ; Crystallography, X-Ray ; Fluoxetine/analogs & derivatives/chemistry/metabolism/pharmacology ; Humans ; *Ion Channel Gating ; Models, Molecular ; Molecular Dynamics Simulation ; Molecular Sequence Data ; Potassium/metabolism ; Potassium Channels, Tandem Pore Domain/antagonists & ; inhibitors/*chemistry/metabolism ; Protein Conformation ; Protein Folding ; Protein Structure, Secondary ; Protein Structure, Tertiary
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  • 10
    Publication Date: 2015-10-10
    Description: Phosphatidylinositol 3-kinase Vps34 complexes regulate intracellular membrane trafficking in endocytic sorting, cytokinesis, and autophagy. We present the 4.4 angstrom crystal structure of the 385-kilodalton endosomal complex II (PIK3C3-CII), consisting of Vps34, Vps15 (p150), Vps30/Atg6 (Beclin 1), and Vps38 (UVRAG). The subunits form a Y-shaped complex, centered on the Vps34 C2 domain. Vps34 and Vps15 intertwine in one arm, where the Vps15 kinase domain engages the Vps34 activation loop to regulate its activity. Vps30 and Vps38 form the other arm that brackets the Vps15/Vps34 heterodimer, suggesting a path for complex assembly. We used hydrogen-deuterium exchange mass spectrometry (HDX-MS) to reveal conformational changes accompanying membrane binding and identify a Vps30 loop that is critical for the ability of complex II to phosphorylate giant liposomes on which complex I is inactive.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601532/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601532/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rostislavleva, Ksenia -- Soler, Nicolas -- Ohashi, Yohei -- Zhang, Lufei -- Pardon, Els -- Burke, John E -- Masson, Glenn R -- Johnson, Chris -- Steyaert, Jan -- Ktistakis, Nicholas T -- Williams, Roger L -- BB/K019155/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MC_U105184308/Medical Research Council/United Kingdom -- PG11/109/29247/British Heart Foundation/United Kingdom -- U105184308/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Oct 9;350(6257):aac7365. doi: 10.1126/science.aac7365.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. ; Structural Biology Research Center, VIB, B-1050 Brussels, Belgium. Structural Biology Brussels, Vrije Universiteit Brussel, B-1050 Brussels, Belgium. ; The Babraham Institute, Cambridge, UK. ; Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. rlw@mrc-lmb.cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26450213" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Membrane/chemistry/*enzymology ; Class III Phosphatidylinositol 3-Kinases/chemistry/*ultrastructure ; Crystallography, X-Ray ; Endosomes/chemistry/*enzymology ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/enzymology ; Vacuolar Sorting Protein VPS15/chemistry/ultrastructure
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  • 11
    Publication Date: 2015-09-19
    Description: Prostate cancer is initially responsive to androgen deprivation, but the effectiveness of androgen receptor (AR) inhibitors in recurrent disease is variable. Biopsy of bone metastases is challenging; hence, sampling circulating tumor cells (CTCs) may reveal drug-resistance mechanisms. We established single-cell RNA-sequencing (RNA-Seq) profiles of 77 intact CTCs isolated from 13 patients (mean six CTCs per patient), by using microfluidic enrichment. Single CTCs from each individual display considerable heterogeneity, including expression of AR gene mutations and splicing variants. Retrospective analysis of CTCs from patients progressing under treatment with an AR inhibitor, compared with untreated cases, indicates activation of noncanonical Wnt signaling (P = 0.0064). Ectopic expression of Wnt5a in prostate cancer cells attenuates the antiproliferative effect of AR inhibition, whereas its suppression in drug-resistant cells restores partial sensitivity, a correlation also evident in an established mouse model. Thus, single-cell analysis of prostate CTCs reveals heterogeneity in signaling pathways that could contribute to treatment failure.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miyamoto, David T -- Zheng, Yu -- Wittner, Ben S -- Lee, Richard J -- Zhu, Huili -- Broderick, Katherine T -- Desai, Rushil -- Fox, Douglas B -- Brannigan, Brian W -- Trautwein, Julie -- Arora, Kshitij S -- Desai, Niyati -- Dahl, Douglas M -- Sequist, Lecia V -- Smith, Matthew R -- Kapur, Ravi -- Wu, Chin-Lee -- Shioda, Toshi -- Ramaswamy, Sridhar -- Ting, David T -- Toner, Mehmet -- Maheswaran, Shyamala -- Haber, Daniel A -- 2R01CA129933/CA/NCI NIH HHS/ -- EB008047/EB/NIBIB NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Sep 18;349(6254):1351-6. doi: 10.1126/science.aab0917.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Urology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Center for Bioengineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. haber@helix.mgh.harvard.edu smaheswaran@mgh.harvard.edu. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. haber@helix.mgh.harvard.edu smaheswaran@mgh.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26383955" target="_blank"〉PubMed〈/a〉
    Keywords: Androgen Antagonists/pharmacology/*therapeutic use ; Animals ; Cell Line, Tumor ; Drug Resistance, Neoplasm/*genetics ; Humans ; Male ; Mice ; Neoplastic Cells, Circulating/drug effects/*metabolism ; Phenylthiohydantoin/*analogs & derivatives/pharmacology/therapeutic use ; Prostate/drug effects/metabolism/pathology ; Prostatic Neoplasms/*drug therapy/*pathology ; Proto-Oncogene Proteins/genetics/metabolism ; RNA Splicing ; Receptors, Androgen/*genetics ; Sequence Analysis, RNA/methods ; Signal Transduction ; Single-Cell Analysis/methods ; Transcriptome ; Wnt Proteins/genetics/*metabolism ; Xenograft Model Antitumor Assays
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  • 12
    Publication Date: 2015-11-07
    Description: Understanding the evolution of sex determination in plants requires identifying the mechanisms underlying the transition from monoecious plants, where male and female flowers coexist, to unisexual individuals found in dioecious species. We show that in melon and cucumber, the androecy gene controls female flower development and encodes a limiting enzyme of ethylene biosynthesis, ACS11. ACS11 is expressed in phloem cells connected to flowers programmed to become female, and ACS11 loss-of-function mutants lead to male plants (androecy). CmACS11 represses the expression of the male promoting gene CmWIP1 to control the development and the coexistence of male and female flowers in monoecious species. Because monoecy can lead to dioecy, we show how a combination of alleles of CmACS11 and CmWIP1 can create artificial dioecy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boualem, Adnane -- Troadec, Christelle -- Camps, Celine -- Lemhemdi, Afef -- Morin, Halima -- Sari, Marie-Agnes -- Fraenkel-Zagouri, Rina -- Kovalski, Irina -- Dogimont, Catherine -- Perl-Treves, Rafael -- Bendahmane, Abdelhafid -- New York, N.Y. -- Science. 2015 Nov 6;350(6261):688-91. doi: 10.1126/science.aac8370.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut National de la Recherche Agronomique (INRA), Institute of Plant Sciences Paris-Saclay, CNRS, Universite Paris-Sud, Universite d'Evry, Universite Paris-Diderot, Batiment 630, 91405, Orsay, France. ; Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS, UMR 8601, Universite Rene Descartes, Paris, France. ; The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. ; INRA, UR 1052, Unite de Genetique et d'Amelioration des Fruits et Legumes, BP 94, F-84143 Montfavet, France. ; Institut National de la Recherche Agronomique (INRA), Institute of Plant Sciences Paris-Saclay, CNRS, Universite Paris-Sud, Universite d'Evry, Universite Paris-Diderot, Batiment 630, 91405, Orsay, France. bendahm@evry.inra.fr.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26542573" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Amino Acid Sequence ; *Biological Evolution ; Cucumis sativus/enzymology/genetics/growth & development ; Cucurbitaceae/enzymology/genetics/*growth & development ; Ethylenes/biosynthesis ; Flowers/enzymology/genetics/*growth & development ; Genes, Plant/genetics/physiology ; Lyases/genetics/*physiology ; Molecular Sequence Data ; Phloem/enzymology/genetics/growth & development ; Plant Proteins/genetics/*physiology ; Sex Determination Processes/*genetics
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  • 13
    Publication Date: 2015-06-20
    Description: G protein-coupled receptors (GPCRs) relay diverse extracellular signals into cells by catalyzing nucleotide release from heterotrimeric G proteins, but the mechanism underlying this quintessential molecular signaling event has remained unclear. Here we use atomic-level simulations to elucidate the nucleotide-release mechanism. We find that the G protein alpha subunit Ras and helical domains-previously observed to separate widely upon receptor binding to expose the nucleotide-binding site-separate spontaneously and frequently even in the absence of a receptor. Domain separation is necessary but not sufficient for rapid nucleotide release. Rather, receptors catalyze nucleotide release by favoring an internal structural rearrangement of the Ras domain that weakens its nucleotide affinity. We use double electron-electron resonance spectroscopy and protein engineering to confirm predictions of our computationally determined mechanism.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dror, Ron O -- Mildorf, Thomas J -- Hilger, Daniel -- Manglik, Aashish -- Borhani, David W -- Arlow, Daniel H -- Philippsen, Ansgar -- Villanueva, Nicolas -- Yang, Zhongyu -- Lerch, Michael T -- Hubbell, Wayne L -- Kobilka, Brian K -- Sunahara, Roger K -- Shaw, David E -- P30EY00331/EY/NEI NIH HHS/ -- R01EY05216/EY/NEI NIH HHS/ -- R01GM083118/GM/NIGMS NIH HHS/ -- T32 GM008294/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 19;348(6241):1361-5. doi: 10.1126/science.aaa5264.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉D. E. Shaw Research, New York, NY 10036, USA. ron.dror@deshawresearch.com david.shaw@deshawresearch.com. ; D. E. Shaw Research, New York, NY 10036, USA. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. ; Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA. ; D. E. Shaw Research, New York, NY 10036, USA. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. ron.dror@deshawresearch.com david.shaw@deshawresearch.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26089515" target="_blank"〉PubMed〈/a〉
    Keywords: GTP-Binding Protein alpha Subunits, Gi-Go/*chemistry ; GTP-Binding Protein alpha Subunits, Gs/*chemistry ; Guanine Nucleotide Exchange Factors/*chemistry ; Humans ; Models, Chemical ; Molecular Dynamics Simulation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, G-Protein-Coupled/*chemistry ; Signal Transduction
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  • 14
    Publication Date: 2015-08-22
    Description: Elucidating the signaling mechanism of strigolactones has been the key to controlling the devastating problem caused by the parasitic plant Striga hermonthica. To overcome the genetic intractability that has previously interfered with identification of the strigolactone receptor, we developed a fluorescence turn-on probe, Yoshimulactone Green (YLG), which activates strigolactone signaling and illuminates signal perception by the strigolactone receptors. Here we describe how strigolactones bind to and act via ShHTLs, the diverged family of alpha/beta hydrolase-fold proteins in Striga. Live imaging using YLGs revealed that a dynamic wavelike propagation of strigolactone perception wakes up Striga seeds. We conclude that ShHTLs function as the strigolactone receptors mediating seed germination in Striga. Our findings enable access to strigolactone receptors and observation of the regulatory dynamics for strigolactone signal transduction in Striga.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tsuchiya, Yuichiro -- Yoshimura, Masahiko -- Sato, Yoshikatsu -- Kuwata, Keiko -- Toh, Shigeo -- Holbrook-Smith, Duncan -- Zhang, Hua -- McCourt, Peter -- Itami, Kenichiro -- Kinoshita, Toshinori -- Hagihara, Shinya -- New York, N.Y. -- Science. 2015 Aug 21;349(6250):864-8. doi: 10.1126/science.aab3831.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. Department of Cell and Systems Biology, University of Toronto, 25 Willcocks Street, Toronto, Ontario M5S 3B2, Canada. yuichiro@itbm.nagoya-u.ac.jp hagi@itbm.nagoya-u.ac.jp. ; Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. ; Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. ; Department of Cell and Systems Biology, University of Toronto, 25 Willcocks Street, Toronto, Ontario M5S 3B2, Canada. ; Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. Japan Science and Technology Agency-Exploratory Research for Advanced Technology, Itami Molecular Nanocarbon Project, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. ; Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. yuichiro@itbm.nagoya-u.ac.jp hagi@itbm.nagoya-u.ac.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26293962" target="_blank"〉PubMed〈/a〉
    Keywords: Fluoresceins/chemistry/metabolism ; Fluorescence ; Fluorescent Dyes/chemistry/metabolism ; *Germination ; Hydrolases/metabolism ; Hydrolysis ; Lactones/*metabolism ; Molecular Imaging/methods ; Molecular Sequence Data ; Plant Growth Regulators/*metabolism ; Plant Proteins/genetics/*metabolism ; Receptors, Cell Surface/genetics/*metabolism ; Seeds/*growth & development/metabolism ; Signal Transduction ; Striga/*growth & development/metabolism
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  • 15
    Publication Date: 2015-01-31
    Description: The mechanistic basis of eukaryotic circadian oscillators in model systems as diverse as Neurospora, Drosophila, and mammalian cells is thought to be a transcription-and-translation-based negative feedback loop, wherein progressive and controlled phosphorylation of one or more negative elements ultimately elicits their own proteasome-mediated degradation, thereby releasing negative feedback and determining circadian period length. The Neurospora crassa circadian negative element FREQUENCY (FRQ) exemplifies such proteins; it is progressively phosphorylated at more than 100 sites, and strains bearing alleles of frq with anomalous phosphorylation display abnormal stability of FRQ that is well correlated with altered periods or apparent arrhythmicity. Unexpectedly, we unveiled normal circadian oscillations that reflect the allelic state of frq but that persist in the absence of typical degradation of FRQ. This manifest uncoupling of negative element turnover from circadian period length determination is not consistent with the consensus eukaryotic circadian model.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432837/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432837/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Larrondo, Luis F -- Olivares-Yanez, Consuelo -- Baker, Christopher L -- Loros, Jennifer J -- Dunlap, Jay C -- P01 GM68087/GM/NIGMS NIH HHS/ -- R01 GM034985/GM/NIGMS NIH HHS/ -- R01 GM083336/GM/NIGMS NIH HHS/ -- R01 GM34985/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 30;347(6221):1257277. doi: 10.1126/science.1257277.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Millennium Nucleus for Fungal Integrative and Synthetic Biology, Departamento de Genetica Molecular y Microbiologia, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Casilla 114-D, Santiago, Chile. Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. jay.c.dunlap@dartmouth.edu llarrondo@bio.puc.cl. ; Millennium Nucleus for Fungal Integrative and Synthetic Biology, Departamento de Genetica Molecular y Microbiologia, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Casilla 114-D, Santiago, Chile. ; Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. ; Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. ; Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. jay.c.dunlap@dartmouth.edu llarrondo@bio.puc.cl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25635104" target="_blank"〉PubMed〈/a〉
    Keywords: Adenine/analogs & derivatives/pharmacology ; Alleles ; *Circadian Clocks ; *Circadian Rhythm ; Feedback, Physiological ; Fungal Proteins/biosynthesis/*genetics/*metabolism ; Half-Life ; Neurospora crassa/*physiology ; Phosphorylation ; Proteasome Endopeptidase Complex/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Stability ; Proteolysis ; Signal Transduction
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  • 16
    Publication Date: 2015-07-25
    Description: In eukaryotic cells, phosphatidylserine (PS) is synthesized in the endoplasmic reticulum (ER) but is highly enriched in the plasma membrane (PM), where it contributes negative charge and to specific recruitment of signaling proteins. This distribution relies on transport mechanisms whose nature remains elusive. Here, we found that the PS transporter Osh6p extracted phosphatidylinositol 4-phosphate (PI4P) and exchanged PS for PI4P between two membranes. We solved the crystal structure of Osh6p:PI4P complex and demonstrated that the transport of PS by Osh6p depends on PI4P recognition in vivo. Finally, we showed that the PI4P-phosphatase Sac1p, by maintaining a PI4P gradient at the ER/PM interface, drove PS transport. Thus, PS transport by oxysterol-binding protein-related protein (ORP)/oxysterol-binding homology (Osh) proteins is fueled by PI4P metabolism through PS/PI4P exchange cycles.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moser von Filseck, Joachim -- Copic, Alenka -- Delfosse, Vanessa -- Vanni, Stefano -- Jackson, Catherine L -- Bourguet, William -- Drin, Guillaume -- New York, N.Y. -- Science. 2015 Jul 24;349(6246):432-6. doi: 10.1126/science.aab1346. Epub 2015 Jul 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut de Pharmacologie Moleculaire et Cellulaire, Universite de Nice Sophia-Antipolis and CNRS, 660 route des lucioles, 06560 Valbonne, France. ; Institut Jacques Monod, CNRS, UMR 7592, Universite Paris Diderot, Sorbonne Paris Cite, F-75013 Paris, France. ; Inserm U1054, 29 rue de Navacelles, 34090 Montpellier, France. CNRS UMR5048, Centre de Biochimie Structurale, 29 rue de Navacelles, 34090 Montpellier, France. ; Institut de Pharmacologie Moleculaire et Cellulaire, Universite de Nice Sophia-Antipolis and CNRS, 660 route des lucioles, 06560 Valbonne, France. drin@ipmc.cnrs.fr.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26206936" target="_blank"〉PubMed〈/a〉
    Keywords: Biological Transport ; Cell Membrane/*metabolism ; Crystallography, X-Ray ; Endoplasmic Reticulum/*metabolism ; Phosphatidylinositol Phosphates/chemistry/*metabolism ; Phosphatidylserines/chemistry/*metabolism ; Phosphoric Monoester Hydrolases/genetics/*metabolism ; Receptors, Steroid/chemistry/genetics/*metabolism ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism
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  • 17
    Publication Date: 2015-02-28
    Description: Ebola virus causes sporadic outbreaks of lethal hemorrhagic fever in humans, but there is no currently approved therapy. Cells take up Ebola virus by macropinocytosis, followed by trafficking through endosomal vesicles. However, few factors controlling endosomal virus movement are known. Here we find that Ebola virus entry into host cells requires the endosomal calcium channels called two-pore channels (TPCs). Disrupting TPC function by gene knockout, small interfering RNAs, or small-molecule inhibitors halted virus trafficking and prevented infection. Tetrandrine, the most potent small molecule that we tested, inhibited infection of human macrophages, the primary target of Ebola virus in vivo, and also showed therapeutic efficacy in mice. Therefore, TPC proteins play a key role in Ebola virus infection and may be effective targets for antiviral therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550587/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550587/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sakurai, Yasuteru -- Kolokoltsov, Andrey A -- Chen, Cheng-Chang -- Tidwell, Michael W -- Bauta, William E -- Klugbauer, Norbert -- Grimm, Christian -- Wahl-Schott, Christian -- Biel, Martin -- Davey, Robert A -- R01 AI063513/AI/NIAID NIH HHS/ -- R01AI063513/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2015 Feb 27;347(6225):995-8. doi: 10.1126/science.1258758.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Texas Biomedical Research Institute, San Antonio, TX, USA. ; The University of Texas Medical Branch, Galveston, TX, USA. ; Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. ; Southwest Research Institute, San Antonio, TX, USA. ; Institute for Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-Universitat Freiburg, Freiburg, Germany. ; Texas Biomedical Research Institute, San Antonio, TX, USA. rdavey@txbiomed.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25722412" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antiviral Agents/*pharmacology/therapeutic use ; BALB 3T3 Cells ; Benzylisoquinolines/pharmacology/therapeutic use ; Calcium Channel Blockers/*pharmacology/therapeutic use ; Calcium Channels/genetics/*physiology ; Ebolavirus/drug effects/*physiology ; Female ; Gene Knockout Techniques ; HeLa Cells ; Hemorrhagic Fever, Ebola/drug therapy/*therapy/virology ; Humans ; Macrophages/drug effects/virology ; Mice ; *Molecular Targeted Therapy ; NADP/analogs & derivatives/metabolism ; RNA Interference ; Signal Transduction ; Verapamil/pharmacology/therapeutic use ; Virus Internalization/*drug effects
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  • 18
    Publication Date: 2015-09-26
    Description: Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) detects intracellular DNA and signals through the adapter protein STING to initiate the antiviral response to DNA viruses. Whether DNA viruses can prevent activation of the cGAS-STING pathway remains largely unknown. Here, we identify the oncogenes of the DNA tumor viruses, including E7 from human papillomavirus (HPV) and E1A from adenovirus, as potent and specific inhibitors of the cGAS-STING pathway. We show that the LXCXE motif of these oncoproteins, which is essential for blockade of the retinoblastoma tumor suppressor, is also important for antagonizing DNA sensing. E1A and E7 bind to STING, and silencing of these oncogenes in human tumor cells restores the cGAS-STING pathway. Our findings reveal a host-virus conflict that may have shaped the evolution of viral oncogenes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lau, Laura -- Gray, Elizabeth E -- Brunette, Rebecca L -- Stetson, Daniel B -- New York, N.Y. -- Science. 2015 Oct 30;350(6260):568-71. doi: 10.1126/science.aab3291. Epub 2015 Sep 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA. ; Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA. stetson@uw.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26405230" target="_blank"〉PubMed〈/a〉
    Keywords: Adenovirus E1A Proteins/chemistry/genetics/*metabolism ; Amino Acid Motifs ; Amino Acid Sequence ; DNA Tumor Viruses/*immunology ; DNA, Neoplasm/immunology ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Evolution, Molecular ; HEK293 Cells ; HeLa Cells ; Host-Pathogen Interactions ; Humans ; Membrane Proteins/*antagonists & inhibitors ; Metabolic Networks and Pathways ; Molecular Sequence Data ; Nucleotides, Cyclic/*antagonists & inhibitors ; Oncogene Proteins, Viral/chemistry/genetics/*metabolism ; Retinoblastoma Protein/antagonists & inhibitors ; *Tumor Escape
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  • 19
    Publication Date: 2015-09-12
    Description: Podophyllotoxin is the natural product precursor of the chemotherapeutic etoposide, yet only part of its biosynthetic pathway is known. We used transcriptome mining in Podophyllum hexandrum (mayapple) to identify biosynthetic genes in the podophyllotoxin pathway. We selected 29 candidate genes to combinatorially express in Nicotiana benthamiana (tobacco) and identified six pathway enzymes, including an oxoglutarate-dependent dioxygenase that closes the core cyclohexane ring of the aryltetralin scaffold. By coexpressing 10 genes in tobacco-these 6 plus 4 previously discovered-we reconstitute the pathway to (-)-4'-desmethylepipodophyllotoxin (the etoposide aglycone), a naturally occurring lignan that is the immediate precursor of etoposide and, unlike podophyllotoxin, a potent topoisomerase inhibitor. Our results enable production of the etoposide aglycone in tobacco and circumvent the need for cultivation of mayapple and semisynthetic epimerization and demethylation of podophyllotoxin.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lau, Warren -- Sattely, Elizabeth S -- DP2 AT008321/AT/NCCIH NIH HHS/ -- R00 GM089985/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Sep 11;349(6253):1224-8. doi: 10.1126/science.aac7202.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA. ; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA. sattely@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26359402" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Biosynthetic Pathways/genetics ; Etoposide/*metabolism ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Plant ; *Genetic Engineering ; Methylation ; Mixed Function Oxygenases/genetics/*metabolism ; Molecular Sequence Data ; Podophyllotoxin/*analogs & derivatives/biosynthesis/*metabolism ; Podophyllum peltatum/*enzymology/genetics ; Tobacco/genetics/*metabolism ; Topoisomerase Inhibitors/*metabolism ; Transcriptome
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  • 20
    Publication Date: 2015-12-19
    Description: Microbial sulfate reduction has governed Earth's biogeochemical sulfur cycle for at least 2.5 billion years. However, the enzymatic mechanisms behind this pathway are incompletely understood, particularly for the reduction of sulfite-a key intermediate in the pathway. This critical reaction is performed by DsrAB, a widespread enzyme also involved in other dissimilatory sulfur metabolisms. Using in vitro assays with an archaeal DsrAB, supported with genetic experiments in a bacterial system, we show that the product of sulfite reduction by DsrAB is a protein-based trisulfide, in which a sulfite-derived sulfur is bridging two conserved cysteines of DsrC. Physiological studies also reveal that sulfate reduction rates are determined by cellular levels of DsrC. Dissimilatory sulfate reduction couples the four-electron reduction of the DsrC trisulfide to energy conservation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Santos, Andre A -- Venceslau, Sofia S -- Grein, Fabian -- Leavitt, William D -- Dahl, Christiane -- Johnston, David T -- Pereira, Ines A C -- New York, N.Y. -- Science. 2015 Dec 18;350(6267):1541-5. doi: 10.1126/science.aad3558.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Instituto de Tecnologia Quimica e Biologica Antonio Xavier, Universidade Nova de Lisboa, Oeiras, Portugal. ; Department of Earth and Planetary Science, Harvard University, Cambridge, MA, USA. ; Institut fur Mikrobiologie & Biotechnologie, Rheinische Friedrich-Wilhelms-Universitat Bonn, Germany. ; Instituto de Tecnologia Quimica e Biologica Antonio Xavier, Universidade Nova de Lisboa, Oeiras, Portugal. ipereira@itqb.unl.pt.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26680199" target="_blank"〉PubMed〈/a〉
    Keywords: Archaeal Proteins/chemistry/*metabolism ; Archaeoglobus fulgidus/*enzymology ; Crystallography, X-Ray ; Cysteine/chemistry/metabolism ; *Energy Metabolism ; Oxidation-Reduction ; Proteins/metabolism ; Sulfates/metabolism ; Sulfides/chemistry/*metabolism ; Sulfites/metabolism ; Sulfur/*metabolism
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  • 21
    Publication Date: 2015-09-01
    Description: Human mutations that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS cell-derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and beta-adrenergic stress, and attenuated growth factor and cell signaling activation. Our findings indicate that titin mutations cause DCM by disrupting critical linkages between sarcomerogenesis and adaptive remodeling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618316/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618316/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hinson, John T -- Chopra, Anant -- Nafissi, Navid -- Polacheck, William J -- Benson, Craig C -- Swist, Sandra -- Gorham, Joshua -- Yang, Luhan -- Schafer, Sebastian -- Sheng, Calvin C -- Haghighi, Alireza -- Homsy, Jason -- Hubner, Norbert -- Church, George -- Cook, Stuart A -- Linke, Wolfgang A -- Chen, Christopher S -- Seidman, J G -- Seidman, Christine E -- EB017103/EB/NIBIB NIH HHS/ -- HG005550/HG/NHGRI NIH HHS/ -- HL007374/HL/NHLBI NIH HHS/ -- HL115553/HL/NHLBI NIH HHS/ -- HL125807/HL/NHLBI NIH HHS/ -- K08 HL125807/HL/NHLBI NIH HHS/ -- T32 HL007208/HL/NHLBI NIH HHS/ -- Department of Health/United Kingdom -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Aug 28;349(6251):982-6. doi: 10.1126/science.aaa5458.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. jthinson@partners.org cseidman@genetics.med.harvard.edu. ; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA. The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA. ; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. ; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. ; Department of Cardiovascular Physiology, Ruhr University Bochum, MA 3/56 D-44780, Bochum, Germany. ; The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. ; Cardiovascular and Metabolic Sciences, Max Delbruck Center for Molecular Medicine, Berlin, Germany. ; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. ; Cardiovascular and Metabolic Sciences, Max Delbruck Center for Molecular Medicine, Berlin, Germany. DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany. ; National Institute for Health Research (NIHR) Biomedical Research Unit in Cardiovascular Disease at Royal Brompton and Harefield National Health Service (NHS) Foundation Trust, Imperial College London, London, UK. National Heart Centre and Duke-National University, Singapore, Singapore. ; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. jthinson@partners.org cseidman@genetics.med.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26315439" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenergic beta-Agonists/pharmacology ; Cardiomyopathy, Dilated/*genetics/pathology/*physiopathology ; Cells, Cultured ; Connectin/chemistry/*genetics/*physiology ; Heart Rate ; Humans ; Induced Pluripotent Stem Cells/*physiology ; Isoproterenol/pharmacology ; Mutant Proteins/chemistry/physiology ; *Mutation, Missense ; Myocardial Contraction ; Myocytes, Cardiac/*physiology ; RNA/genetics/metabolism ; Sarcomeres/*physiology/ultrastructure ; Sequence Analysis, RNA ; Signal Transduction ; Stress, Physiological
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  • 22
    Publication Date: 2015-03-07
    Description: Chemokines are small proteins that function as immune modulators through activation of chemokine G protein-coupled receptors (GPCRs). Several viruses also encode chemokines and chemokine receptors to subvert the host immune response. How protein ligands activate GPCRs remains unknown. We report the crystal structure at 2.9 angstrom resolution of the human cytomegalovirus GPCR US28 in complex with the chemokine domain of human CX3CL1 (fractalkine). The globular body of CX3CL1 is perched on top of the US28 extracellular vestibule, whereas its amino terminus projects into the central core of US28. The transmembrane helices of US28 adopt an active-state-like conformation. Atomic-level simulations suggest that the agonist-independent activity of US28 may be due to an amino acid network evolved in the viral GPCR to destabilize the receptor's inactive state.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445376/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445376/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Burg, John S -- Ingram, Jessica R -- Venkatakrishnan, A J -- Jude, Kevin M -- Dukkipati, Abhiram -- Feinberg, Evan N -- Angelini, Alessandro -- Waghray, Deepa -- Dror, Ron O -- Ploegh, Hidde L -- Garcia, K Christopher -- DP1 GM106409/GM/NIGMS NIH HHS/ -- R01 GM097015/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Mar 6;347(6226):1113-7. doi: 10.1126/science.aaa5026.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Computer Science, Stanford University, Stanford, CA 94305, USA. Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA. ; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. kcgarcia@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25745166" target="_blank"〉PubMed〈/a〉
    Keywords: CCR5 Receptor Antagonists/chemistry ; Chemokine CX3CL1/*chemistry ; Crystallography, X-Ray ; Cyclohexanes/chemistry ; Humans ; Ligands ; Piperidines/chemistry ; Protein Binding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, CXCR4/antagonists & inhibitors ; Receptors, Chemokine/agonists/*chemistry ; Triazoles/chemistry ; Viral Proteins/agonists/*chemistry
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  • 23
    Publication Date: 2015-06-13
    Description: Cell division progresses to anaphase only after all chromosomes are connected to spindle microtubules through kinetochores and the spindle assembly checkpoint (SAC) is satisfied. We show that the amino-terminal localization module of the SAC protein kinase MPS1 (monopolar spindle 1) directly interacts with the HEC1 (highly expressed in cancer 1) calponin homology domain in the NDC80 (nuclear division cycle 80) kinetochore complex in vitro, in a phosphorylation-dependent manner. Microtubule polymers disrupted this interaction. In cells, MPS1 binding to kinetochores or to ectopic NDC80 complexes was prevented by end-on microtubule attachment, independent of known kinetochore protein-removal mechanisms. Competition for kinetochore binding between SAC proteins and microtubules provides a direct and perhaps evolutionarily conserved way to detect a properly organized spindle ready for cell division.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hiruma, Yoshitaka -- Sacristan, Carlos -- Pachis, Spyridon T -- Adamopoulos, Athanassios -- Kuijt, Timo -- Ubbink, Marcellus -- von Castelmur, Eleonore -- Perrakis, Anastassis -- Kops, Geert J P L -- New York, N.Y. -- Science. 2015 Jun 12;348(6240):1264-7. doi: 10.1126/science.aaa4055. Epub 2015 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. ; Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. ; Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. ; Leiden Institute of Chemistry, Leiden University, Post Office Box 9502, 2300 RA Leiden, Netherlands. ; Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. g.j.p.l.kops@umcutrecht.nl a.perrakis@nki.nl. ; Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. g.j.p.l.kops@umcutrecht.nl a.perrakis@nki.nl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26068855" target="_blank"〉PubMed〈/a〉
    Keywords: Anaphase ; Binding, Competitive ; Calcium-Binding Proteins/genetics/metabolism ; *Cell Cycle Checkpoints ; Cell Cycle Proteins/*metabolism ; HeLa Cells ; Humans ; Kinetochores/*metabolism ; Microfilament Proteins/genetics/metabolism ; Microtubules/*metabolism ; Nuclear Proteins/chemistry/*metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases/*metabolism ; Protein-Tyrosine Kinases/*metabolism ; Signal Transduction ; Spindle Apparatus/*metabolism
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  • 24
    Publication Date: 2015-10-03
    Description: Body-size constancy and symmetry are signs of developmental stability. Yet, it is unclear exactly how developing animals buffer size variation. Drosophila insulin-like peptide Dilp8 is responsive to growth perturbations and controls homeostatic mechanisms that coordinately adjust growth and maturation to maintain size within the normal range. Here we show that Lgr3 is a Dilp8 receptor. Through the use of functional and adenosine 3',5'-monophosphate assays, we defined a pair of Lgr3 neurons that mediate homeostatic regulation. These neurons have extensive axonal arborizations, and genetic and green fluorescent protein reconstitution across synaptic partners show that these neurons connect with the insulin-producing cells and prothoracicotropic hormone-producing neurons to attenuate growth and maturation. This previously unrecognized circuit suggests how growth and maturation rate are matched and co-regulated according to Dilp8 signals to stabilize organismal size.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vallejo, Diana M -- Juarez-Carreno, Sergio -- Bolivar, Jorge -- Morante, Javier -- Dominguez, Maria -- OD010949-10/OD/NIH HHS/ -- P40OD018537/OD/NIH HHS/ -- R01-GM084947/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Nov 13;350(6262):aac6767. doi: 10.1126/science.aac6767. Epub 2015 Oct 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Instituto de Neurociencias, Consejo Superior de Investigaciones Cientificas and Universidad Miguel Hernandez, Campus de Sant Joan, Apartado 18, 03550 Sant Joan, Alicante, Spain. ; Departamento de Biomedicina, Biotecnologia y Salud Publica, Facultad de Ciencias, Universidad de Cadiz, Poligono Rio San Pedro s/n, 11510 Puerto Real, Spain. ; Instituto de Neurociencias, Consejo Superior de Investigaciones Cientificas and Universidad Miguel Hernandez, Campus de Sant Joan, Apartado 18, 03550 Sant Joan, Alicante, Spain. m.dominguez@umh.es j.morante@umh.es.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26429885" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Monophosphate/metabolism ; Animals ; Body Size ; Brain/cytology/*growth & development/metabolism ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster/*growth & development/metabolism ; Homeostasis ; Insect Hormones/genetics/metabolism ; Insulin/*metabolism ; Intercellular Signaling Peptides and Proteins/genetics/*metabolism ; Nerve Net/cytology/metabolism ; Neurons/*metabolism ; Receptors, G-Protein-Coupled/genetics/*metabolism ; Receptors, Peptide/genetics/*metabolism ; Signal Transduction ; Synapses/metabolism
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  • 25
    Publication Date: 2015-03-31
    Description: The occurrence of Ebola virus (EBOV) in West Africa during 2013-2015 is unprecedented. Early reports suggested that in this outbreak EBOV is mutating twice as fast as previously observed, which indicates the potential for changes in transmissibility and virulence and could render current molecular diagnostics and countermeasures ineffective. We have determined additional full-length sequences from two clusters of imported EBOV infections into Mali, and we show that the nucleotide substitution rate (9.6 x 10(-4) substitutions per site per year) is consistent with rates observed in Central African outbreaks. In addition, overall variation among all genotypes observed remains low. Thus, our data indicate that EBOV is not undergoing rapid evolution in humans during the current outbreak. This finding has important implications for outbreak response and public health decisions and should alleviate several previously raised concerns.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hoenen, T -- Safronetz, D -- Groseth, A -- Wollenberg, K R -- Koita, O A -- Diarra, B -- Fall, I S -- Haidara, F C -- Diallo, F -- Sanogo, M -- Sarro, Y S -- Kone, A -- Togo, A C G -- Traore, A -- Kodio, M -- Dosseh, A -- Rosenke, K -- de Wit, E -- Feldmann, F -- Ebihara, H -- Munster, V J -- Zoon, K C -- Feldmann, H -- Sow, S -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2015 Apr 3;348(6230):117-9. doi: 10.1126/science.aaa5646. Epub 2015 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Hamilton, MT 59840, USA. ; Bioinformatics and Computational Biosciences Branch, NIAID, NIH, Bethesda, MD 20892, USA. ; Center of Research and Training for HIV and Tuberculosis, University of Science, Technique and Technologies of Bamako, Mali. ; World Health Organization Office, Bamako, Mali. ; Centre des Operations d'Urgence, Centre pour le Developpement des Vaccins (CVD-Mali), Centre National d'Appui a la lutte contre la Maladie, Ministere de la Sante et de l'Hygiene Publique, Bamako, Mali. ; World Health Organization Inter-Country Support Team, Ouagadougou, Burkina Faso. ; Rocky Mountain Veterinary Branch, Division of Intramural Research, NIAID, NIH, Hamilton, MT 59840, USA. ; Office of the Scientific Director, NIAID, NIH, Bethesda, MD 20895, USA. ; Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Hamilton, MT 59840, USA. feldmannh@niaid.nih.gov ssow@medicine.umaryland.edu. ; Centre des Operations d'Urgence, Centre pour le Developpement des Vaccins (CVD-Mali), Centre National d'Appui a la lutte contre la Maladie, Ministere de la Sante et de l'Hygiene Publique, Bamako, Mali. feldmannh@niaid.nih.gov ssow@medicine.umaryland.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25814067" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Disease Outbreaks ; Ebolavirus/classification/*genetics/isolation & purification ; Genotype ; Hemorrhagic Fever, Ebola/epidemiology/*virology ; Humans ; Mali/epidemiology ; Molecular Sequence Data ; *Mutation Rate ; Phylogeny
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  • 26
    Publication Date: 2015-09-01
    Description: DNA strand exchange plays a central role in genetic recombination across all kingdoms of life, but the physical basis for these reactions remains poorly defined. Using single-molecule imaging, we found that bacterial RecA and eukaryotic Rad51 and Dmc1 all stabilize strand exchange intermediates in precise three-nucleotide steps. Each step coincides with an energetic signature (0.3 kBT) that is conserved from bacteria to humans. Triplet recognition is strictly dependent on correct Watson-Crick pairing. Rad51, RecA, and Dmc1 can all step over mismatches, but only Dmc1 can stabilize mismatched triplets. This finding provides insight into why eukaryotes have evolved a meiosis-specific recombinase. We propose that canonical Watson-Crick base triplets serve as the fundamental unit of pairing interactions during DNA recombination.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580133/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580133/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Ja Yil -- Terakawa, Tsuyoshi -- Qi, Zhi -- Steinfeld, Justin B -- Redding, Sy -- Kwon, YoungHo -- Gaines, William A -- Zhao, Weixing -- Sung, Patrick -- Greene, Eric C -- CA146940/CA/NCI NIH HHS/ -- GM074739/GM/NIGMS NIH HHS/ -- R01 CA146940/CA/NCI NIH HHS/ -- R01 ES015252/ES/NIEHS NIH HHS/ -- R01 GM074739/GM/NIGMS NIH HHS/ -- R01ES015252/ES/NIEHS NIH HHS/ -- T32 GM007367/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Aug 28;349(6251):977-81. doi: 10.1126/science.aab2666.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. ; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. Department of Biophysics, Kyoto University, Sakyo, Kyoto, Japan. ; Department of Chemistry, Columbia University, New York, NY, USA. ; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA. ; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. Howard Hughes Medical Institute, Columbia University, New York, NY, USA. ecg2108@cumc.columbia.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26315438" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Base Pairing ; Base Sequence ; Cell Cycle Proteins/chemistry/metabolism ; DNA/*chemistry/*metabolism ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/chemistry/metabolism ; Escherichia coli Proteins/chemistry/metabolism ; Evolution, Molecular ; *Homologous Recombination ; Humans ; Meiosis ; Molecular Dynamics Simulation ; Molecular Sequence Data ; Rad51 Recombinase/chemistry/*metabolism ; Rec A Recombinases/chemistry/*metabolism ; Recombinases/chemistry/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; Thermodynamics
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  • 27
    Publication Date: 2015-11-21
    Description: Stabilization of the hypoxia-inducible factor 1 (HIF-1) increases life span and health span in nematodes through an unknown mechanism. We report that neuronal stabilization of HIF-1 mediates these effects in Caenorhabditis elegans through a cell nonautonomous signal to the intestine, which results in activation of the xenobiotic detoxification enzyme flavin-containing monooxygenase-2 (FMO-2). This prolongevity signal requires the serotonin biosynthetic enzyme TPH-1 in neurons and the serotonin receptor SER-7 in the intestine. Intestinal FMO-2 is also activated by dietary restriction (DR) and is necessary for DR-mediated life-span extension, which suggests that this enzyme represents a point of convergence for two distinct longevity pathways. FMOs are conserved in eukaryotes and induced by multiple life span-extending interventions in mice, which suggests that these enzymes may play a critical role in promoting health and longevity across phyla.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Leiser, Scott F -- Miller, Hillary -- Rossner, Ryan -- Fletcher, Marissa -- Leonard, Alison -- Primitivo, Melissa -- Rintala, Nicholas -- Ramos, Fresnida J -- Miller, Dana L -- Kaeberlein, Matt -- P30AG013280/AG/NIA NIH HHS/ -- R00AGA0033050/PHS HHS/ -- R01AG038518/AG/NIA NIH HHS/ -- T32AG000057/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2015 Dec 11;350(6266):1375-8. doi: 10.1126/science.aac9257. Epub 2015 Nov 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, University of Washington, Seattle, WA 98195, USA. ; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. ; Department of Pathology, University of Washington, Seattle, WA 98195, USA. kaeber@uw.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26586189" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Caenorhabditis elegans/genetics/metabolism/*physiology ; Caenorhabditis elegans Proteins/chemistry/genetics/metabolism/*physiology ; Diet ; Intestines/*enzymology ; Longevity/genetics/*physiology ; Mice ; Neurons/*metabolism ; Oxygenases/genetics/*physiology ; Protein Stability ; RNA Interference ; Receptors, Serotonin/metabolism ; Signal Transduction ; Transcription Factors/chemistry/*metabolism ; Tryptophan Hydroxylase/metabolism
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  • 28
    Publication Date: 2015-01-03
    Description: Variation in vectorial capacity for human malaria among Anopheles mosquito species is determined by many factors, including behavior, immunity, and life history. To investigate the genomic basis of vectorial capacity and explore new avenues for vector control, we sequenced the genomes of 16 anopheline mosquito species from diverse locations spanning ~100 million years of evolution. Comparative analyses show faster rates of gene gain and loss, elevated gene shuffling on the X chromosome, and more intron losses, relative to Drosophila. Some determinants of vectorial capacity, such as chemosensory genes, do not show elevated turnover but instead diversify through protein-sequence changes. This dynamism of anopheline genes and genomes may contribute to their flexible capacity to take advantage of new ecological niches, including adapting to humans as primary hosts.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380271/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380271/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Neafsey, Daniel E -- Waterhouse, Robert M -- Abai, Mohammad R -- Aganezov, Sergey S -- Alekseyev, Max A -- Allen, James E -- Amon, James -- Arca, Bruno -- Arensburger, Peter -- Artemov, Gleb -- Assour, Lauren A -- Basseri, Hamidreza -- Berlin, Aaron -- Birren, Bruce W -- Blandin, Stephanie A -- Brockman, Andrew I -- Burkot, Thomas R -- Burt, Austin -- Chan, Clara S -- Chauve, Cedric -- Chiu, Joanna C -- Christensen, Mikkel -- Costantini, Carlo -- Davidson, Victoria L M -- Deligianni, Elena -- Dottorini, Tania -- Dritsou, Vicky -- Gabriel, Stacey B -- Guelbeogo, Wamdaogo M -- Hall, Andrew B -- Han, Mira V -- Hlaing, Thaung -- Hughes, Daniel S T -- Jenkins, Adam M -- Jiang, Xiaofang -- Jungreis, Irwin -- Kakani, Evdoxia G -- Kamali, Maryam -- Kemppainen, Petri -- Kennedy, Ryan C -- Kirmitzoglou, Ioannis K -- Koekemoer, Lizette L -- Laban, Njoroge -- Langridge, Nicholas -- Lawniczak, Mara K N -- Lirakis, Manolis -- Lobo, Neil F -- Lowy, Ernesto -- MacCallum, Robert M -- Mao, Chunhong -- Maslen, Gareth -- Mbogo, Charles -- McCarthy, Jenny -- Michel, Kristin -- Mitchell, Sara N -- Moore, Wendy -- Murphy, Katherine A -- Naumenko, Anastasia N -- Nolan, Tony -- Novoa, Eva M -- O'Loughlin, Samantha -- Oringanje, Chioma -- Oshaghi, Mohammad A -- Pakpour, Nazzy -- Papathanos, Philippos A -- Peery, Ashley N -- Povelones, Michael -- Prakash, Anil -- Price, David P -- Rajaraman, Ashok -- Reimer, Lisa J -- Rinker, David C -- Rokas, Antonis -- Russell, Tanya L -- Sagnon, N'Fale -- Sharakhova, Maria V -- Shea, Terrance -- Simao, Felipe A -- Simard, Frederic -- Slotman, Michel A -- Somboon, Pradya -- Stegniy, Vladimir -- Struchiner, Claudio J -- Thomas, Gregg W C -- Tojo, Marta -- Topalis, Pantelis -- Tubio, Jose M C -- Unger, Maria F -- Vontas, John -- Walton, Catherine -- Wilding, Craig S -- Willis, Judith H -- Wu, Yi-Chieh -- Yan, Guiyun -- Zdobnov, Evgeny M -- Zhou, Xiaofan -- Catteruccia, Flaminia -- Christophides, George K -- Collins, Frank H -- Cornman, Robert S -- Crisanti, Andrea -- Donnelly, Martin J -- Emrich, Scott J -- Fontaine, Michael C -- Gelbart, William -- Hahn, Matthew W -- Hansen, Immo A -- Howell, Paul I -- Kafatos, Fotis C -- Kellis, Manolis -- Lawson, Daniel -- Louis, Christos -- Luckhart, Shirley -- Muskavitch, Marc A T -- Ribeiro, Jose M -- Riehle, Michael A -- Sharakhov, Igor V -- Tu, Zhijian -- Zwiebel, Laurence J -- Besansky, Nora J -- 092654/Wellcome Trust/United Kingdom -- R01 AI050243/AI/NIAID NIH HHS/ -- R01 AI063508/AI/NIAID NIH HHS/ -- R01 AI073745/AI/NIAID NIH HHS/ -- R01 AI076584/AI/NIAID NIH HHS/ -- R01 AI080799/AI/NIAID NIH HHS/ -- R01 AI104956/AI/NIAID NIH HHS/ -- R21 AI101459/AI/NIAID NIH HHS/ -- R56 AI107263/AI/NIAID NIH HHS/ -- SC1 AI109055/AI/NIAID NIH HHS/ -- U19 AI089686/AI/NIAID NIH HHS/ -- U19 AI110818/AI/NIAID NIH HHS/ -- U41 HG007234/HG/NHGRI NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 2;347(6217):1258522. doi: 10.1126/science.1258522. Epub 2014 Nov 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genome Sequencing and Analysis Program, Broad Institute, 415 Main Street, Cambridge, MA 02142, USA. neafsey@broadinstitute.org nbesansk@nd.edu. ; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar Street, Cambridge, MA 02139, USA. The Broad Institute of Massachusetts Institute of Technology and Harvard, 415 Main Street, Cambridge, MA 02142, USA. Department of Genetic Medicine and Development, University of Geneva Medical School, Rue Michel-Servet 1, 1211 Geneva, Switzerland. Swiss Institute of Bioinformatics, Rue Michel-Servet 1, 1211 Geneva, Switzerland. ; Department of Medical Entomology and Vector Control, School of Public Health and Institute of Health Researches, Tehran University of Medical Sciences, Tehran, Iran. ; George Washington University, Department of Mathematics and Computational Biology Institute, 45085 University Drive, Ashburn, VA 20147, USA. ; European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. ; National Vector Borne Disease Control Programme, Ministry of Health, Tafea Province, Vanuatu. ; Department of Public Health and Infectious Diseases, Division of Parasitology, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy. ; Department of Biological Sciences, California State Polytechnic-Pomona, 3801 West Temple Avenue, Pomona, CA 91768, USA. ; Tomsk State University, 36 Lenina Avenue, Tomsk, Russia. ; Department of Computer Science and Engineering, Eck Institute for Global Health, 211B Cushing Hall, University of Notre Dame, Notre Dame, IN 46556, USA. ; Genome Sequencing and Analysis Program, Broad Institute, 415 Main Street, Cambridge, MA 02142, USA. ; Inserm, U963, F-67084 Strasbourg, France. CNRS, UPR9022, IBMC, F-67084 Strasbourg, France. ; Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. ; Faculty of Medicine, Health and Molecular Science, Australian Institute of Tropical Health Medicine, James Cook University, Cairns 4870, Australia. ; Department of Life Sciences, Imperial College London, Silwood Park Campus, Ascot SL5 7PY, UK. ; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar Street, Cambridge, MA 02139, USA. The Broad Institute of Massachusetts Institute of Technology and Harvard, 415 Main Street, Cambridge, MA 02142, USA. ; Department of Mathematics, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada. ; Department of Entomology and Nematology, One Shields Avenue, University of California-Davis, Davis, CA 95616, USA. ; Institut de Recherche pour le Developpement, Unites Mixtes de Recherche Maladies Infectieuses et Vecteurs Ecologie, Genetique, Evolution et Controle, 911, Avenue Agropolis, BP 64501 Montpellier, France. ; Division of Biology, Kansas State University, 271 Chalmers Hall, Manhattan, KS 66506, USA. ; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Hellas, Nikolaou Plastira 100 GR-70013, Heraklion, Crete, Greece. ; Centre of Functional Genomics, University of Perugia, Perugia, Italy. ; Genomics Platform, Broad Institute, 415 Main Street, Cambridge, MA 02142, USA. ; Centre National de Recherche et de Formation sur le Paludisme, Ouagadougou 01 BP 2208, Burkina Faso. ; Program of Genetics, Bioinformatics, and Computational Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. ; School of Life Sciences, University of Nevada, Las Vegas, NV 89154, USA. ; Department of Medical Research, No. 5 Ziwaka Road, Dagon Township, Yangon 11191, Myanmar. ; European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA. ; Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA 02467, USA. ; Department of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. Program of Genetics, Bioinformatics, and Computational Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. ; Harvard School of Public Health, Department of Immunology and Infectious Diseases, Boston, MA 02115, USA. Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Universita degli Studi di Perugia, Perugia, Italy. ; Department of Entomology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. ; Computational Evolutionary Biology Group, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK. ; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143, USA. ; Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. Bioinformatics Research Laboratory, Department of Biological Sciences, New Campus, University of Cyprus, CY 1678 Nicosia, Cyprus. ; Wits Research Institute for Malaria, Faculty of Health Sciences, and Vector Control Reference Unit, National Institute for Communicable Diseases of the National Health Laboratory Service, Sandringham 2131, Johannesburg, South Africa. ; National Museums of Kenya, P.O. Box 40658-00100, Nairobi, Kenya. ; Department of Biology, University of Crete, 700 13 Heraklion, Greece. ; Eck Institute for Global Health and Department of Biological Sciences, University of Notre Dame, 317 Galvin Life Sciences Building, Notre Dame, IN 46556, USA. ; Virginia Bioinformatics Institute, 1015 Life Science Circle, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. ; Kenya Medical Research Institute-Wellcome Trust Research Programme, Centre for Geographic Medicine Research - Coast, P.O. Box 230-80108, Kilifi, Kenya. ; Harvard School of Public Health, Department of Immunology and Infectious Diseases, Boston, MA 02115, USA. ; Department of Entomology, 1140 East South Campus Drive, Forbes 410, University of Arizona, Tucson, AZ 85721, USA. ; Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, One Shields Avenue, Davis, CA 95616, USA. ; Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. Centre of Functional Genomics, University of Perugia, Perugia, Italy. ; Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA. ; Regional Medical Research Centre NE, Indian Council of Medical Research, P.O. Box 105, Dibrugarh-786 001, Assam, India. ; Department of Biology, New Mexico State University, Las Cruces, NM 88003, USA. Molecular Biology Program, New Mexico State University, Las Cruces, NM 88003, USA. ; Department of Vector Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK. ; Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN 37235, USA. ; Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN 37235, USA. Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA. ; Department of Genetic Medicine and Development, University of Geneva Medical School, Rue Michel-Servet 1, 1211 Geneva, Switzerland. Swiss Institute of Bioinformatics, Rue Michel-Servet 1, 1211 Geneva, Switzerland. ; Department of Entomology, Texas A&M University, College Station, TX 77807, USA. ; Department of Parasitology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. ; Fundacao Oswaldo Cruz, Avenida Brasil 4365, RJ Brazil. Instituto de Medicina Social, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil. ; School of Informatics and Computing, Indiana University, Bloomington, IN 47405, USA. ; Department of Physiology, School of Medicine, Center for Research in Molecular Medicine and Chronic Diseases, Instituto de Investigaciones Sanitarias, University of Santiago de Compostela, Santiago de Compostela, A Coruna, Spain. ; Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, CB10 1SA, UK. ; School of Natural Sciences and Psychology, Liverpool John Moores University, Liverpool L3 3AF, UK. ; Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA. ; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar Street, Cambridge, MA 02139, USA. The Broad Institute of Massachusetts Institute of Technology and Harvard, 415 Main Street, Cambridge, MA 02142, USA. Department of Computer Science, Harvey Mudd College, Claremont, CA 91711, USA. ; Program in Public Health, College of Health Sciences, University of California, Irvine, Hewitt Hall, Irvine, CA 92697, USA. ; Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA. ; Department of Vector Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK. Malaria Programme, Wellcome Trust Sanger Institute, Cambridge CB10 1SJ, UK. ; Eck Institute for Global Health and Department of Biological Sciences, University of Notre Dame, 317 Galvin Life Sciences Building, Notre Dame, IN 46556, USA. Centre of Evolutionary and Ecological Studies (Marine Evolution and Conservation group), University of Groningen, Nijenborgh 7, NL-9747 AG Groningen, Netherlands. ; Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA. ; Department of Biology, Indiana University, Bloomington, IN 47405, USA. School of Informatics and Computing, Indiana University, Bloomington, IN 47405, USA. ; Centers for Disease Control and Prevention, 1600 Clifton Road NE MSG49, Atlanta, GA 30329, USA. ; Department of Biology, University of Crete, 700 13 Heraklion, Greece. Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Hellas, Nikolaou Plastira 100 GR-70013, Heraklion, Crete, Greece. Centre of Functional Genomics, University of Perugia, Perugia, Italy. ; Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA 02467, USA. Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA. ; Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, 12735 Twinbrook Parkway, Rockville, MD 20852, USA. ; Department of Entomology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. Program of Genetics, Bioinformatics, and Computational Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. ; Program of Genetics, Bioinformatics, and Computational Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. Department of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. ; Departments of Biological Sciences and Pharmacology, Institutes for Chemical Biology, Genetics and Global Health, Vanderbilt University and Medical Center, Nashville, TN 37235, USA. ; Eck Institute for Global Health and Department of Biological Sciences, University of Notre Dame, 317 Galvin Life Sciences Building, Notre Dame, IN 46556, USA. neafsey@broadinstitute.org nbesansk@nd.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25554792" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anopheles/classification/*genetics ; Base Sequence ; Chromosomes, Insect/genetics ; Drosophila/genetics ; *Evolution, Molecular ; *Genome, Insect ; Humans ; Insect Vectors/classification/*genetics ; Malaria/*transmission ; Molecular Sequence Data ; Phylogeny ; Sequence Alignment
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  • 29
    Publication Date: 2015-10-17
    Description: Transcriptional enhancers direct precise on-off patterns of gene expression during development. To explore the basis for this precision, we conducted a high-throughput analysis of the Otx-a enhancer, which mediates expression in the neural plate of Ciona embryos in response to fibroblast growth factor (FGF) signaling and a localized GATA determinant. We provide evidence that enhancer specificity depends on submaximal recognition motifs having reduced binding affinities ("suboptimization"). Native GATA and ETS (FGF) binding sites contain imperfect matches to consensus motifs. Perfect matches mediate robust but ectopic patterns of gene expression. The native sites are not arranged at optimal intervals, and subtle changes in their spacing alter enhancer activity. Multiple tiers of enhancer suboptimization produce specific, but weak, patterns of expression, and we suggest that clusters of weak enhancers, including certain "superenhancers," circumvent this trade-off in specificity and activity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Farley, Emma K -- Olson, Katrina M -- Zhang, Wei -- Brandt, Alexander J -- Rokhsar, Daniel S -- Levine, Michael S -- GM46638/GM/NIGMS NIH HHS/ -- NS076542/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2015 Oct 16;350(6258):325-8. doi: 10.1126/science.aac6948.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, Division of Genetics, Genomics and Development, Center for Integrative Genomics, University of California, Berkeley, CA 94720-3200, USA. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA. msl2@princeton.edu ekfarley@princeton.edu. ; Department of Molecular and Cell Biology, Division of Genetics, Genomics and Development, Center for Integrative Genomics, University of California, Berkeley, CA 94720-3200, USA. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA. ; Department of Medicine, University of California, San Diego, CA 92093-0688, USA. ; Department of Chemistry, University of California, Berkeley, CA 94720-3200, USA. ; Department of Molecular and Cell Biology, Division of Genetics, Genomics and Development, Center for Integrative Genomics, University of California, Berkeley, CA 94720-3200, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26472909" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Binding Sites ; Ciona intestinalis/genetics/*growth & development ; Consensus Sequence ; Enhancer Elements, Genetic/genetics/*physiology ; Fas-Associated Death Domain Protein/metabolism ; Fibroblast Growth Factors/*metabolism ; GATA Transcription Factors/*metabolism ; *Gene Expression Regulation, Developmental ; Molecular Sequence Data ; Organ Specificity/genetics/physiology ; Otx Transcription Factors/*metabolism
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  • 30
    Publication Date: 2015-01-13
    Description: NADPH/NADP(+) (the reduced form of NADP(+)/nicotinamide adenine dinucleotide phosphate) homeostasis is critical for countering oxidative stress in cells. Nicotinamide nucleotide transhydrogenase (TH), a membrane enzyme present in both bacteria and mitochondria, couples the proton motive force to the generation of NADPH. We present the 2.8 A crystal structure of the transmembrane proton channel domain of TH from Thermus thermophilus and the 6.9 A crystal structure of the entire enzyme (holo-TH). The membrane domain crystallized as a symmetric dimer, with each protomer containing a putative proton channel. The holo-TH is a highly asymmetric dimer with the NADP(H)-binding domain (dIII) in two different orientations. This unusual arrangement suggests a catalytic mechanism in which the two copies of dIII alternatively function in proton translocation and hydride transfer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479213/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479213/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Leung, Josephine H -- Schurig-Briccio, Lici A -- Yamaguchi, Mutsuo -- Moeller, Arne -- Speir, Jeffrey A -- Gennis, Robert B -- Stout, Charles D -- 1R01GM103838-01A1/GM/NIGMS NIH HHS/ -- 5R01GM061545/GM/NIGMS NIH HHS/ -- GM073197/GM/NIGMS NIH HHS/ -- GM095600/GM/NIGMS NIH HHS/ -- P41 GM103310/GM/NIGMS NIH HHS/ -- P41GM103310/GM/NIGMS NIH HHS/ -- R01 GM061545/GM/NIGMS NIH HHS/ -- R01 GM095600/GM/NIGMS NIH HHS/ -- R01 GM103838/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 9;347(6218):178-81. doi: 10.1126/science.1260451.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. ; Department of Biochemistry, University of Illinois, Urbana, IL 61801, USA. ; National Resource for Automated Molecular Microscopy, The Scripps Research Institute, La Jolla, CA 92037, USA. ; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. dave@scripps.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25574024" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Crystallography, X-Ray ; Molecular Sequence Data ; NADP Transhydrogenases/*chemistry ; Protein Multimerization ; Protein Structure, Tertiary ; *Protons ; Thermus thermophilus/enzymology
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  • 31
    Publication Date: 2015-06-27
    Description: Pigment-protein and pigment-pigment interactions are of fundamental importance to the light-harvesting and photoprotective functions essential to oxygenic photosynthesis. The orange carotenoid protein (OCP) functions as both a sensor of light and effector of photoprotective energy dissipation in cyanobacteria. We report the atomic-resolution structure of an active form of the OCP consisting of the N-terminal domain and a single noncovalently bound carotenoid pigment. The crystal structure, combined with additional solution-state structural data, reveals that OCP photoactivation is accompanied by a 12 angstrom translocation of the pigment within the protein and a reconfiguration of carotenoid-protein interactions. Our results identify the origin of the photochromic changes in the OCP triggered by light and reveal the structural determinants required for interaction with the light-harvesting antenna during photoprotection.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Leverenz, Ryan L -- Sutter, Markus -- Wilson, Adjele -- Gupta, Sayan -- Thurotte, Adrien -- Bourcier de Carbon, Celine -- Petzold, Christopher J -- Ralston, Corie -- Perreau, Francois -- Kirilovsky, Diana -- Kerfeld, Cheryl A -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Jun 26;348(6242):1463-6. doi: 10.1126/science.aaa7234.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MSU-DOE Plant Research Laboratory, Michigan State University, East Lansing, MI 48824, USA. ; MSU-DOE Plant Research Laboratory, Michigan State University, East Lansing, MI 48824, USA. Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. ; Commissariat a l'Energie Atomique (CEA), Institut de Biologie et Technologies de Saclay (iBiTec-S), 91191 Gif-sur-Yvette, France. Centre National de la Recherche Scientifique (CNRS), I2BC, UMR 9198, 91191 Gif-sur-Yvette, France. ; Berkeley Center for Structural Biology, Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. ; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. ; INRA, Institut Jean-Pierre Bourgin, UMR 1318, ERL CNRS 3559, Saclay Plant Sciences, RD10, F-78026 Versailles, France. ; MSU-DOE Plant Research Laboratory, Michigan State University, East Lansing, MI 48824, USA. Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Department of Plant and Microbial Biology, University of California, Berkeley, CA 94720, USA. ckerfeld@lbl.gov.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26113721" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/metabolism ; Canthaxanthin/*chemistry/metabolism ; Crystallography, X-Ray ; Models, Chemical ; *Photosynthesis ; Phycobilisomes/*chemistry ; Protein Structure, Secondary ; Protein Transport ; Synechocystis/*metabolism
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  • 32
    Publication Date: 2015-07-15
    Description: The carnivoran giant panda has a specialized bamboo diet, to which its alimentary tract is poorly adapted. Measurements of daily energy expenditure across five captive and three wild pandas averaged 5.2 megajoules (MJ)/day, only 37.7% of the predicted value (13.8 MJ/day). For the wild pandas, the mean was 6.2 MJ/day, or 45% of the mammalian expectation. Pandas achieve this exceptionally low expenditure in part by reduced sizes of several vital organs and low physical activity. In addition, circulating levels of thyroid hormones thyroxine (T4) and triiodothyronine (T3) averaged 46.9 and 64%, respectively, of the levels expected for a eutherian mammal of comparable size. A giant panda-unique mutation in the DUOX2 gene, critical for thyroid hormone synthesis, might explain these low thyroid hormone levels. A combination of morphological, behavioral, physiological, and genetic adaptations, leading to low energy expenditure, likely enables giant pandas to survive on a bamboo diet.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nie, Yonggang -- Speakman, John R -- Wu, Qi -- Zhang, Chenglin -- Hu, Yibo -- Xia, Maohua -- Yan, Li -- Hambly, Catherine -- Wang, Lu -- Wei, Wei -- Zhang, Jinguo -- Wei, Fuwen -- New York, N.Y. -- Science. 2015 Jul 10;349(6244):171-4. doi: 10.1126/science.aab2413.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. ; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China. Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, Scotland, UK. ; Beijing Key Laboratory of Captive Wildlife Technologies, Beijing Zoo, Beijing, China. ; Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, Scotland, UK. ; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China. ; Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. weifw@ioz.ac.cn.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26160943" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Body Temperature ; Cattle ; Chromosomes, Human, Pair 15/genetics ; Diet/veterinary ; Dogs ; *Eating ; Energy Metabolism/genetics/*physiology ; Gastrointestinal Tract ; Genetic Variation ; Humans ; Mice ; Molecular Sequence Data ; Motor Activity ; NADPH Oxidase/*genetics ; Organ Size ; Sasa ; Thyroxine/blood ; Triiodothyronine/blood ; Ursidae/anatomy & histology/*genetics/*physiology
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  • 33
    Publication Date: 2015-01-31
    Description: The 18-kilodalton translocator protein (TSPO), proposed to be a key player in cholesterol transport into mitochondria, is highly expressed in steroidogenic tissues, metastatic cancer, and inflammatory and neurological diseases such as Alzheimer's and Parkinson's. TSPO ligands, including benzodiazepine drugs, are implicated in regulating apoptosis and are extensively used in diagnostic imaging. We report crystal structures (at 1.8, 2.4, and 2.5 angstrom resolution) of TSPO from Rhodobacter sphaeroides and a mutant that mimics the human Ala(147)--〉Thr(147) polymorphism associated with psychiatric disorders and reduced pregnenolone production. Crystals obtained in the lipidic cubic phase reveal the binding site of an endogenous porphyrin ligand and conformational effects of the mutation. The three crystal structures show the same tightly interacting dimer and provide insights into the controversial physiological role of TSPO and how the mutation affects cholesterol binding.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Fei -- Liu, Jian -- Zheng, Yi -- Garavito, R Michael -- Ferguson-Miller, Shelagh -- ACB-12002/PHS HHS/ -- AGM-12006/PHS HHS/ -- GM094625/GM/NIGMS NIH HHS/ -- GM26916/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 30;347(6221):555-8. doi: 10.1126/science.1260590.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. ; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. fergus20@msu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25635101" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Bacterial Proteins/*chemistry/*metabolism ; Binding Sites ; Cholesterol/metabolism ; Crystallography, X-Ray ; Humans ; Hydrogen Bonding ; Isoquinolines/metabolism ; Ligands ; Membrane Transport Proteins/*chemistry/*metabolism ; Models, Molecular ; Molecular Sequence Data ; Mutant Proteins/chemistry ; Polymorphism, Single Nucleotide ; Porphyrins/metabolism ; Protein Conformation ; Protein Multimerization ; Protein Structure, Secondary ; Protoporphyrins/metabolism ; Receptors, GABA/chemistry/genetics ; Rhodobacter sphaeroides/*chemistry
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  • 34
    Publication Date: 2015-01-03
    Description: Lysosomes are crucial cellular organelles for human health that function in digestion and recycling of extracellular and intracellular macromolecules. We describe a signaling role for lysosomes that affects aging. In the worm Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, which promoted longevity by activating the nuclear hormone receptors NHR-49 and NHR-80. We used high-throughput metabolomic analysis to identify several lipids in which abundance was increased in worms constitutively overexpressing LIPL-4. Among them, oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins, activated transcription of target genes of NHR-49 and NHR-80, and promoted longevity in C. elegans. These findings reveal a lysosome-to-nucleus signaling pathway that promotes longevity and suggest a function of lysosomes as signaling organelles in metazoans.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425353/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425353/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Folick, Andrew -- Oakley, Holly D -- Yu, Yong -- Armstrong, Eric H -- Kumari, Manju -- Sanor, Lucas -- Moore, David D -- Ortlund, Eric A -- Zechner, Rudolf -- Wang, Meng C -- F30 AG046043/AG/NIA NIH HHS/ -- F30AG046043/AG/NIA NIH HHS/ -- R00 AG034988/AG/NIA NIH HHS/ -- R00AG034988/AG/NIA NIH HHS/ -- R01 AG045183/AG/NIA NIH HHS/ -- R01 DK095750/DK/NIDDK NIH HHS/ -- R01AG045183/AG/NIA NIH HHS/ -- R01DK095750/DK/NIDDK NIH HHS/ -- T32 GM008602/GM/NIGMS NIH HHS/ -- T32GM008602/GM/NIGMS NIH HHS/ -- T32HD055200/HD/NICHD NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 2;347(6217):83-6. doi: 10.1126/science.1258857.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. ; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. ; Department of Biochemistry, Discovery and Developmental Therapeutics, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. ; Institute of Molecular Biosciences, University of Graz, Graz, A-8010, Austria. ; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA. ; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. ; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. wmeng@bcm.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25554789" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Animals ; Caenorhabditis elegans/genetics/*physiology ; Caenorhabditis elegans Proteins/genetics/*metabolism ; Cell Nucleus/metabolism ; Lipase/metabolism ; Lipid Metabolism ; Longevity/genetics/*physiology ; Lysosomes/*metabolism ; Molecular Chaperones/genetics/*metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism ; Signal Transduction
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  • 35
    Publication Date: 2015-06-06
    Description: Retroviruses depend on self-assembly of their capsid proteins (core particle) to yield infectious mature virions. Despite the essential role of the retroviral core, its high polymorphism has hindered high-resolution structural analyses. Here, we report the x-ray structure of the native capsid (CA) protein from bovine leukemia virus. CA is organized as hexamers that deviate substantially from sixfold symmetry, yet adjust to make two-dimensional pseudohexagonal arrays that mimic mature retroviral cores. Intra- and interhexameric quasi-equivalent contacts are uncovered, with flexible trimeric lateral contacts among hexamers, yet preserving very similar dimeric interfaces making the lattice. The conformation of each capsid subunit in the hexamer is therefore dictated by long-range interactions, revealing how the hexamers can also assemble into closed core particles, a relevant feature of retrovirus biology.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Obal, G -- Trajtenberg, F -- Carrion, F -- Tome, L -- Larrieux, N -- Zhang, X -- Pritsch, O -- Buschiazzo, A -- New York, N.Y. -- Science. 2015 Jul 3;349(6243):95-8. doi: 10.1126/science.aaa5182. Epub 2015 Jun 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Pasteur de Montevideo, Unit of Protein Biophysics, Mataojo 2020, 11400, Montevideo, Uruguay. Departamento de Inmunobiologia, Facultad de Medicina, Universidad de la Republica, Avenida General Flores 2125, 11800, Montevideo, Uruguay. ; Institut Pasteur de Montevideo, Unit of Protein Crystallography, Mataojo 2020, 11400, Montevideo, Uruguay. ; Institut Pasteur de Montevideo, Unit of Protein Biophysics, Mataojo 2020, 11400, Montevideo, Uruguay. ; Institut Pasteur, Unite de Virologie Structurale, Departement de Virologie and CNRS Unite Mixte de Recherche 3569, 28, Rue du Docteur Roux, 75015, Paris, France. ; Institut Pasteur de Montevideo, Unit of Protein Biophysics, Mataojo 2020, 11400, Montevideo, Uruguay. Departamento de Inmunobiologia, Facultad de Medicina, Universidad de la Republica, Avenida General Flores 2125, 11800, Montevideo, Uruguay. pritsch@pasteur.edu.uy alebus@pasteur.edu.uy. ; Institut Pasteur de Montevideo, Unit of Protein Crystallography, Mataojo 2020, 11400, Montevideo, Uruguay. Institut Pasteur, Department of Structural Biology and Chemistry, 25, Rue du Dr Roux, 75015, Paris, France. pritsch@pasteur.edu.uy alebus@pasteur.edu.uy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26044299" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Capsid/*chemistry ; Capsid Proteins/*chemistry/genetics ; Cattle ; Crystallography, X-Ray ; Leukemia Virus, Bovine/*chemistry/genetics ; Molecular Sequence Data ; Mutation ; Protein Multimerization ; Protein Structure, Secondary
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  • 36
    Publication Date: 2015-09-01
    Description: A challenge of synthetic biology is the creation of cooperative microbial systems that exhibit population-level behaviors. Such systems use cellular signaling mechanisms to regulate gene expression across multiple cell types. We describe the construction of a synthetic microbial consortium consisting of two distinct cell types-an "activator" strain and a "repressor" strain. These strains produced two orthogonal cell-signaling molecules that regulate gene expression within a synthetic circuit spanning both strains. The two strains generated emergent, population-level oscillations only when cultured together. Certain network topologies of the two-strain circuit were better at maintaining robust oscillations than others. The ability to program population-level dynamics through the genetic engineering of multiple cooperative strains points the way toward engineering complex synthetic tissues and organs with multiple cell types.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597888/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597888/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Ye -- Kim, Jae Kyoung -- Hirning, Andrew J -- Josic, Kresimir -- Bennett, Matthew R -- R01 GM104974/GM/NIGMS NIH HHS/ -- R01GM104974/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Aug 28;349(6251):986-9. doi: 10.1126/science.aaa3794.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biosciences, Rice University, Houston, TX 77005, USA. ; Department of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea. Mathematical Biosciences Institute, The Ohio State University, Columbus, OH 43210, USA. ; Department of Mathematics, University of Houston, Houston, TX 77204, USA. Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA. ; Department of Biosciences, Rice University, Houston, TX 77005, USA. Institute of Biosciences and Bioengineering, Rice University, Houston, TX 77005, USA. matthew.bennett@rice.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26315440" target="_blank"〉PubMed〈/a〉
    Keywords: 4-Butyrolactone/analogs & derivatives/metabolism ; Escherichia coli/*genetics/*physiology ; Escherichia coli Proteins/genetics/metabolism ; Feedback, Physiological ; *Gene Expression Regulation, Bacterial ; *Gene Regulatory Networks ; Genetic Engineering ; Lab-On-A-Chip Devices ; Microbial Consortia/*genetics/*physiology ; Microbial Interactions ; Models, Biological ; Promoter Regions, Genetic ; Quorum Sensing ; Signal Transduction ; Synthetic Biology ; Transcription, Genetic
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  • 37
    Publication Date: 2015-01-13
    Description: XRCC4 and XLF are two structurally related proteins that function in DNA double-strand break (DSB) repair. Here, we identify human PAXX (PAralog of XRCC4 and XLF, also called C9orf142) as a new XRCC4 superfamily member and show that its crystal structure resembles that of XRCC4. PAXX interacts directly with the DSB-repair protein Ku and is recruited to DNA-damage sites in cells. Using RNA interference and CRISPR-Cas9 to generate PAXX(-/-) cells, we demonstrate that PAXX functions with XRCC4 and XLF to mediate DSB repair and cell survival in response to DSB-inducing agents. Finally, we reveal that PAXX promotes Ku-dependent DNA ligation in vitro and assembly of core nonhomologous end-joining (NHEJ) factors on damaged chromatin in cells. These findings identify PAXX as a new component of the NHEJ machinery.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338599/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338599/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ochi, Takashi -- Blackford, Andrew N -- Coates, Julia -- Jhujh, Satpal -- Mehmood, Shahid -- Tamura, Naoka -- Travers, Jon -- Wu, Qian -- Draviam, Viji M -- Robinson, Carol V -- Blundell, Tom L -- Jackson, Stephen P -- 11224/Cancer Research UK/United Kingdom -- 268536/European Research Council/International -- A11224/Cancer Research UK/United Kingdom -- C28598/A9787/Cancer Research UK/United Kingdom -- C6/A11224/Cancer Research UK/United Kingdom -- C6946/A14492/Cancer Research UK/United Kingdom -- WT092096/Wellcome Trust/United Kingdom -- WT093167/Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2015 Jan 9;347(6218):185-8. doi: 10.1126/science.1261971.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. ; Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK. ; Physical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QZ, UK. ; Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK. ; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. s.jackson@gurdon.cam.ac.uk tlb20@cam.ac.uk. ; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. s.jackson@gurdon.cam.ac.uk tlb20@cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25574025" target="_blank"〉PubMed〈/a〉
    Keywords: Antigens, Nuclear/*metabolism ; Cell Line, Tumor ; Crystallography, X-Ray ; *DNA Breaks, Double-Stranded ; *DNA End-Joining Repair ; DNA Repair Enzymes/metabolism ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Humans ; Protein Structure, Secondary ; RNA Interference
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  • 38
    Publication Date: 2015-08-08
    Description: Cytoplasmic aggregation of TDP-43, accompanied by its nuclear clearance, is a key common pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, a limited understanding of this RNA-binding protein (RBP) impedes the clarification of pathogenic mechanisms underlying TDP-43 proteinopathy. In contrast to RBPs that regulate splicing of conserved exons, we found that TDP-43 repressed the splicing of nonconserved cryptic exons, maintaining intron integrity. When TDP-43 was depleted from mouse embryonic stem cells, these cryptic exons were spliced into messenger RNAs, often disrupting their translation and promoting nonsense-mediated decay. Moreover, enforced repression of cryptic exons prevented cell death in TDP-43-deficient cells. Furthermore, repression of cryptic exons was impaired in ALS-FTD cases, suggesting that this splicing defect could potentially underlie TDP-43 proteinopathy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ling, Jonathan P -- Pletnikova, Olga -- Troncoso, Juan C -- Wong, Philip C -- P50AG05146/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2015 Aug 7;349(6248):650-5. doi: 10.1126/science.aab0983.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. ; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. ; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. wong@jhmi.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26250685" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Base Sequence ; Cells, Cultured ; Cysteine Endopeptidases/genetics ; DNA-Binding Proteins/genetics/*physiology ; Embryonic Stem Cells ; Exons/*genetics ; Frontotemporal Dementia/*genetics ; Gene Knockout Techniques ; HeLa Cells ; Humans ; Mice ; Molecular Sequence Data ; Protein Isoforms/genetics ; *RNA Splicing ; RNA Stability ; RNA, Messenger/metabolism ; Sequence Analysis, DNA
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  • 39
    Publication Date: 2015-04-18
    Description: Protective CD8(+) T cell-mediated immunity requires a massive expansion in cell number and the development of long-lived memory cells. Using forward genetics in mice, we identified an orphan protein named lymphocyte expansion molecule (LEM) that promoted antigen-dependent CD8(+) T cell proliferation, effector function, and memory cell generation in response to infection with lymphocytic choriomeningitis virus. Generation of LEM-deficient mice confirmed these results. Through interaction with CR6 interacting factor (CRIF1), LEM controlled the levels of oxidative phosphorylation (OXPHOS) complexes and respiration, resulting in the production of pro-proliferative mitochondrial reactive oxygen species (mROS). LEM provides a link between immune activation and the expansion of protective CD8(+) T cells driven by OXPHOS and represents a pathway for the restoration of long-term protective immunity based on metabolically modified cytotoxic CD8(+) T cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Okoye, Isobel -- Wang, Lihui -- Pallmer, Katharina -- Richter, Kirsten -- Ichimura, Takahuru -- Haas, Robert -- Crouse, Josh -- Choi, Onjee -- Heathcote, Dean -- Lovo, Elena -- Mauro, Claudio -- Abdi, Reza -- Oxenius, Annette -- Rutschmann, Sophie -- Ashton-Rickardt, Philip G -- A9995/Cancer Research UK/United Kingdom -- AI091930/AI/NIAID NIH HHS/ -- AI45108/AI/NIAID NIH HHS/ -- FS/12/38/29640/British Heart Foundation/United Kingdom -- G0700795/Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2015 May 29;348(6238):995-1001. doi: 10.1126/science.aaa7516. Epub 2015 Apr 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section of Immunobiology, Division of Inflammation and Immunology, Department of Medicine, Faculty of Medicine, Imperial College London, Exhibition Road, London SW7 2AZ, UK. ; Institute of Microbiology, Eidgenossische Technische Hochschule Zurich (ETHZ), Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland. ; Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02215, USA. ; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK. ; Section of Immunobiology, Division of Inflammation and Immunology, Department of Medicine, Faculty of Medicine, Imperial College London, Exhibition Road, London SW7 2AZ, UK. Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02215, USA. p.ashton-rickardt@imperial.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25883318" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CD8-Positive T-Lymphocytes/*immunology/*metabolism ; Cell Cycle Proteins/metabolism ; Cell Respiration ; Immunity, Cellular ; *Immunologic Memory ; Lymphocytic Choriomeningitis/immunology ; Lymphocytic choriomeningitis virus/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/*metabolism ; Mitochondrial Proteins/genetics/*metabolism ; Molecular Sequence Data ; Oxidative Phosphorylation ; Reactive Oxygen Species/metabolism
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  • 40
    Publication Date: 2015-06-27
    Description: Circadian clocks generate slow and ordered cellular dynamics but consist of fast-moving bio-macromolecules; consequently, the origins of the overall slowness remain unclear. We identified the adenosine triphosphate (ATP) catalytic region [adenosine triphosphatase (ATPase)] in the amino-terminal half of the clock protein KaiC as the minimal pacemaker that controls the in vivo frequency of the cyanobacterial clock. Crystal structures of the ATPase revealed that the slowness of this ATPase arises from sequestration of a lytic water molecule in an unfavorable position and coupling of ATP hydrolysis to a peptide isomerization with high activation energy. The slow ATPase is coupled with another ATPase catalyzing autodephosphorylation in the carboxyl-terminal half of KaiC, yielding the circadian response frequency of intermolecular interactions with other clock-related proteins that influences the transcription and translation cycle.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abe, Jun -- Hiyama, Takuya B -- Mukaiyama, Atsushi -- Son, Seyoung -- Mori, Toshifumi -- Saito, Shinji -- Osako, Masato -- Wolanin, Julie -- Yamashita, Eiki -- Kondo, Takao -- Akiyama, Shuji -- New York, N.Y. -- Science. 2015 Jul 17;349(6245):312-6. doi: 10.1126/science.1261040. Epub 2015 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Center of Integrative Molecular Systems (CIMoS), Institute for Molecular Science, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. ; Research Center of Integrative Molecular Systems (CIMoS), Institute for Molecular Science, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. Department of Functional Molecular Science, SOKENDAI (The Graduate University for Advanced Studies), 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. ; Division of Biological Science, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. ; Department of Functional Molecular Science, SOKENDAI (The Graduate University for Advanced Studies), 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. Department of Theoretical and Computational Molecular Science, Institute for Molecular Science, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. ; Research Center of Integrative Molecular Systems (CIMoS), Institute for Molecular Science, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. Department of Functional Molecular Science, SOKENDAI (The Graduate University for Advanced Studies), 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. Department of Theoretical and Computational Molecular Science, Institute for Molecular Science, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. ; Research Center of Integrative Molecular Systems (CIMoS), Institute for Molecular Science, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. PSL Research University, Chimie ParisTech, 75005 Paris, France. ; Institute for Protein Research, Osaka University, 3-2 Yamada-oka, Suita 565-0871, Japan. ; Research Center of Integrative Molecular Systems (CIMoS), Institute for Molecular Science, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. Department of Functional Molecular Science, SOKENDAI (The Graduate University for Advanced Studies), 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. akiyamas@ims.ac.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26113637" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/*chemistry/genetics ; Adenosine Triphosphate/chemistry ; Bacterial Proteins/*chemistry/genetics ; Catalysis ; *Catalytic Domain ; Circadian Clocks/*physiology ; *Circadian Rhythm ; Circadian Rhythm Signaling Peptides and Proteins/*chemistry/genetics ; Crystallography, X-Ray ; Hydrolysis ; Synechococcus/enzymology/*physiology
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  • 41
    Publication Date: 2015-06-27
    Description: Cardiac progenitor cells are multipotent and give rise to cardiac endothelium, smooth muscle, and cardiomyocytes. Here, we define and characterize the cardiomyoblast intermediate that is committed to the cardiomyocyte fate, and we characterize the niche signals that regulate commitment. Cardiomyoblasts express Hopx, which functions to coordinate local Bmp signals to inhibit the Wnt pathway, thus promoting cardiomyogenesis. Hopx integrates Bmp and Wnt signaling by physically interacting with activated Smads and repressing Wnt genes. The identification of the committed cardiomyoblast that retains proliferative potential will inform cardiac regenerative therapeutics. In addition, Bmp signals characterize adult stem cell niches in other tissues where Hopx-mediated inhibition of Wnt is likely to contribute to stem cell quiescence and to explain the role of Hopx as a tumor suppressor.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jain, Rajan -- Li, Deqiang -- Gupta, Mudit -- Manderfield, Lauren J -- Ifkovits, Jamie L -- Wang, Qiaohong -- Liu, Feiyan -- Liu, Ying -- Poleshko, Andrey -- Padmanabhan, Arun -- Raum, Jeffrey C -- Li, Li -- Morrisey, Edward E -- Lu, Min Min -- Won, Kyoung-Jae -- Epstein, Jonathan A -- 5-T32-GM-007170/GM/NIGMS NIH HHS/ -- K08 HL119553/HL/NHLBI NIH HHS/ -- K08 HL119553-02/HL/NHLBI NIH HHS/ -- R01 HL071546/HL/NHLBI NIH HHS/ -- U01 HL100405/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 26;348(6242):aaa6071. doi: 10.1126/science.aaa6071.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell and Developmental Biology, Penn Cardiovascular Institute, Institute of Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. ; Department of Genetics, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. ; Department of Cell and Developmental Biology, Penn Cardiovascular Institute, Institute of Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. epsteinj@upenn.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26113728" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Bone Morphogenetic Proteins/genetics/*metabolism ; Cell Lineage/genetics ; Gene Expression ; *Gene Expression Regulation, Developmental ; Heart/*embryology ; Homeodomain Proteins/genetics/*metabolism ; Mice ; Mice, Mutant Strains ; Molecular Sequence Data ; Muscle, Smooth/cytology/metabolism ; Myoblasts, Cardiac/cytology/*metabolism ; Organogenesis/*genetics ; Stem Cell Niche/genetics/physiology ; Tumor Suppressor Proteins/genetics/*metabolism ; Wnt Signaling Pathway/*genetics
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  • 42
    Publication Date: 2015-01-09
    Description: The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar adenosine triphosphatase-dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. Here, we identify SLC38A9, an uncharacterized protein with sequence similarity to amino acid transporters, as a lysosomal transmembrane protein that interacts with the Rag guanosine triphosphatases (GTPases) and Ragulator in an amino acid-sensitive fashion. SLC38A9 transports arginine with a high Michaelis constant, and loss of SLC38A9 represses mTORC1 activation by amino acids, particularly arginine. Overexpression of SLC38A9 or just its Ragulator-binding domain makes mTORC1 signaling insensitive to amino acid starvation but not to Rag activity. Thus, SLC38A9 functions upstream of the Rag GTPases and is an excellent candidate for being an arginine sensor for the mTORC1 pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295826/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295826/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Shuyu -- Tsun, Zhi-Yang -- Wolfson, Rachel L -- Shen, Kuang -- Wyant, Gregory A -- Plovanich, Molly E -- Yuan, Elizabeth D -- Jones, Tony D -- Chantranupong, Lynne -- Comb, William -- Wang, Tim -- Bar-Peled, Liron -- Zoncu, Roberto -- Straub, Christoph -- Kim, Choah -- Park, Jiwon -- Sabatini, Bernardo L -- Sabatini, David M -- AI47389/AI/NIAID NIH HHS/ -- F30 CA180754/CA/NCI NIH HHS/ -- F31 AG044064/AG/NIA NIH HHS/ -- F31 CA180271/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R37 AI047389/AI/NIAID NIH HHS/ -- T32 GM007287/GM/NIGMS NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Jan 9;347(6218):188-94. doi: 10.1126/science.1257132. Epub 2015 Jan 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. ; Harvard Medical School, 260 Longwood Avenue, Boston, MA 02115, USA. ; Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. ; Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. sabatini@wi.mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25567906" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amino Acid Transport Systems/chemistry/genetics/*metabolism ; Arginine/deficiency/*metabolism ; HEK293 Cells ; Humans ; Lysosomes/*enzymology ; Molecular Sequence Data ; Monomeric GTP-Binding Proteins/*metabolism ; Multiprotein Complexes/*metabolism ; Protein Structure, Tertiary ; Signal Transduction ; TOR Serine-Threonine Kinases/*metabolism
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  • 43
    Publication Date: 2015-02-01
    Description: During virus infection, the adaptor proteins MAVS and STING transduce signals from the cytosolic nucleic acid sensors RIG-I and cGAS, respectively, to induce type I interferons (IFNs) and other antiviral molecules. Here we show that MAVS and STING harbor two conserved serine and threonine clusters that are phosphorylated by the kinases IKK and/or TBK1 in response to stimulation. Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1. We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. These results reveal that phosphorylation of innate adaptor proteins is an essential and conserved mechanism that selectively recruits IRF3 to activate the type I IFN pathway.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Siqi -- Cai, Xin -- Wu, Jiaxi -- Cong, Qian -- Chen, Xiang -- Li, Tuo -- Du, Fenghe -- Ren, Junyao -- Wu, You-Tong -- Grishin, Nick V -- Chen, Zhijian J -- AI-93967/AI/NIAID NIH HHS/ -- GM-094575/GM/NIGMS NIH HHS/ -- GM-63692/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Mar 13;347(6227):aaa2630. doi: 10.1126/science.aaa2630. Epub 2015 Jan 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. ; Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. ; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Howard Hughes Medical Institute (HHMI), University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. ; Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Howard Hughes Medical Institute (HHMI), University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. ; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Howard Hughes Medical Institute (HHMI), University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. zhijian.chen@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25636800" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/chemistry/*metabolism ; Adaptor Proteins, Vesicular Transport/chemistry/*metabolism ; Amino Acid Sequence ; Animals ; Cell Line ; Humans ; I-kappa B Kinase/metabolism ; Interferon Regulatory Factor-3/chemistry/*metabolism ; Interferon-alpha/biosynthesis ; Interferon-beta/biosynthesis ; Membrane Proteins/chemistry/*metabolism ; Mice ; Molecular Sequence Data ; Phosphorylation ; Protein Binding ; Protein Multimerization ; Protein-Serine-Threonine Kinases/metabolism ; Recombinant Proteins/metabolism ; Sendai virus/physiology ; Serine/metabolism ; Signal Transduction ; Ubiquitination ; Vesiculovirus/physiology
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  • 44
    Publication Date: 2015-07-18
    Description: Secretion of the cytokine interleukin-1beta (IL-1beta) by macrophages, a major driver of pathogenesis in atherosclerosis, requires two steps: Priming signals promote transcription of immature IL-1beta, and then endogenous "danger" signals activate innate immune signaling complexes called inflammasomes to process IL-1beta for secretion. Although cholesterol crystals are known to act as danger signals in atherosclerosis, what primes IL-1beta transcription remains elusive. Using a murine model of atherosclerosis, we found that cholesterol crystals acted both as priming and danger signals for IL-1beta production. Cholesterol crystals triggered neutrophils to release neutrophil extracellular traps (NETs). NETs primed macrophages for cytokine release, activating T helper 17 (TH17) cells that amplify immune cell recruitment in atherosclerotic plaques. Therefore, danger signals may drive sterile inflammation, such as that seen in atherosclerosis, through their interactions with neutrophils.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Warnatsch, Annika -- Ioannou, Marianna -- Wang, Qian -- Papayannopoulos, Venizelos -- MC_UP_1202/13/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Jul 17;349(6245):316-20. doi: 10.1126/science.aaa8064. Epub 2015 Jul 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Mill Hill Laboratory, Francis Crick Institute, London NW7 1AA, UK. ; Mill Hill Laboratory, Francis Crick Institute, London NW7 1AA, UK. veni.p@crick.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26185250" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apolipoproteins E/genetics ; Atherosclerosis/*immunology ; Cells, Cultured ; Cholesterol/chemistry/immunology ; Disease Models, Animal ; Extracellular Traps/*immunology ; Humans ; Inflammasomes/immunology ; Inflammation/immunology ; Interleukin-1beta/*biosynthesis/genetics ; Macrophages/*immunology ; Mice ; Mice, Mutant Strains ; Neutrophils/*immunology ; Signal Transduction ; Th17 Cells/immunology ; Transcription, Genetic
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  • 45
    Publication Date: 2015-01-03
    Description: Enterovirus D68 (EV-D68) is a member of Picornaviridae and is a causative agent of recent outbreaks of respiratory illness in children in the United States. We report here the crystal structures of EV-D68 and its complex with pleconaril, a capsid-binding compound that had been developed as an anti-rhinovirus drug. The hydrophobic drug-binding pocket in viral protein 1 contained density that is consistent with a fatty acid of about 10 carbon atoms. This density could be displaced by pleconaril. We also showed that pleconaril inhibits EV-D68 at a half-maximal effective concentration of 430 nanomolar and might, therefore, be a possible drug candidate to alleviate EV-D68 outbreaks.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4307789/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4307789/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Yue -- Sheng, Ju -- Fokine, Andrei -- Meng, Geng -- Shin, Woong-Hee -- Long, Feng -- Kuhn, Richard J -- Kihara, Daisuke -- Rossmann, Michael G -- AI11219/AI/NIAID NIH HHS/ -- R24 GM111072/GM/NIGMS NIH HHS/ -- R37 AI011219/AI/NIAID NIH HHS/ -- RR007707/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 2;347(6217):71-4. doi: 10.1126/science.1261962.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, Hockmeyer Hall of Structural Biology, 240 South Martin Jischke Drive, Purdue University, West Lafayette, IN 47907, USA. ; Department of Biological Sciences, Hockmeyer Hall of Structural Biology, 240 South Martin Jischke Drive, Purdue University, West Lafayette, IN 47907, USA. Department of Computer Science, 305 North University Street, Purdue University, West Lafayette, IN 47907, USA. ; Department of Biological Sciences, Hockmeyer Hall of Structural Biology, 240 South Martin Jischke Drive, Purdue University, West Lafayette, IN 47907, USA. mr@purdue.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25554786" target="_blank"〉PubMed〈/a〉
    Keywords: Antiviral Agents/*chemistry/pharmacology/therapeutic use ; Capsid/*chemistry/drug effects/ultrastructure ; Child ; Crystallography, X-Ray ; Enterovirus D, Human/*chemistry/drug effects/ultrastructure ; Enterovirus Infections/drug therapy/epidemiology/*virology ; Humans ; Hydrophobic and Hydrophilic Interactions ; Oxadiazoles/*chemistry/pharmacology/therapeutic use ; Respiratory Tract Diseases/drug therapy/epidemiology/*virology ; United States/epidemiology ; Viral Proteins/chemistry/ultrastructure
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  • 46
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2015-07-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Garber, Ken -- New York, N.Y. -- Science. 2015 Jul 10;349(6244):129. doi: 10.1126/science.349.6244.129.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26160924" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Oxidoreductases/chemistry/metabolism ; Collagen/metabolism ; Copper/*metabolism ; Humans ; Melanoma/drug therapy/pathology ; Neoplasms/*drug therapy/pathology ; Proto-Oncogene Proteins B-raf/*antagonists & inhibitors/genetics ; Signal Transduction ; Skin Diseases/drug therapy/pathology
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  • 47
    Publication Date: 2015-08-22
    Description: Nuclear pore complexes (NPCs) conduct nucleocytoplasmic transport and gain transport selectivity through nucleoporin FG domains. Here, we report a structural analysis of the FG Nup62*58*54 complex, which is a crucial component of the transport system. It comprises a approximately 13 nanometer-long trimerization interface with an unusual 2W3F coil, a canonical heterotrimeric coiled coil, and a kink that enforces a compact six-helix bundle. Nup54 also contains a ferredoxin-like domain. We further identified a heterotrimeric Nup93-binding module for NPC anchorage. The quaternary structure alternations in the Nup62 complex, which were previously proposed to trigger a general gating of the NPC, are incompatible with the trimer structure. We suggest that the highly elongated Nup62 complex projects barrier-forming FG repeats far into the central NPC channel, supporting a barrier that guards the entire cross section.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chug, Hema -- Trakhanov, Sergei -- Hulsmann, Bastian B -- Pleiner, Tino -- Gorlich, Dirk -- New York, N.Y. -- Science. 2015 Oct 2;350(6256):106-10. doi: 10.1126/science.aac7420. Epub 2015 Aug 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular Logistics, Max Planck Institute for Biophysical Chemistry, Gottingen, Germany. ; Department of Cellular Logistics, Max Planck Institute for Biophysical Chemistry, Gottingen, Germany. goerlich@mpibpc.mpg.de.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26292704" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Crystallography, X-Ray ; Databases, Protein ; Nuclear Pore/chemistry/*ultrastructure ; Nuclear Pore Complex Proteins/chemistry/*ultrastructure ; Protein Structure, Tertiary ; Xenopus Proteins/chemistry/ultrastructure ; Xenopus laevis
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  • 48
    Publication Date: 2015-12-19
    Description: Voltage-gated sodium (Nav) channels propagate action potentials in excitable cells. Accordingly, Nav channels are therapeutic targets for many cardiovascular and neurological disorders. Selective inhibitors have been challenging to design because the nine mammalian Nav channel isoforms share high sequence identity and remain recalcitrant to high-resolution structural studies. Targeting the human Nav1.7 channel involved in pain perception, we present a protein-engineering strategy that has allowed us to determine crystal structures of a novel receptor site in complex with isoform-selective antagonists. GX-936 and related inhibitors bind to the activated state of voltage-sensor domain IV (VSD4), where their anionic aryl sulfonamide warhead engages the fourth arginine gating charge on the S4 helix. By opposing VSD4 deactivation, these compounds inhibit Nav1.7 through a voltage-sensor trapping mechanism, likely by stabilizing inactivated states of the channel. Residues from the S2 and S3 helices are key determinants of isoform selectivity, and bound phospholipids implicate the membrane as a modulator of channel function and pharmacology. Our results help to elucidate the molecular basis of voltage sensing and establish structural blueprints to design selective Nav channel antagonists.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ahuja, Shivani -- Mukund, Susmith -- Deng, Lunbin -- Khakh, Kuldip -- Chang, Elaine -- Ho, Hoangdung -- Shriver, Stephanie -- Young, Clint -- Lin, Sophia -- Johnson, J P Jr -- Wu, Ping -- Li, Jun -- Coons, Mary -- Tam, Christine -- Brillantes, Bobby -- Sampang, Honorio -- Mortara, Kyle -- Bowman, Krista K -- Clark, Kevin R -- Estevez, Alberto -- Xie, Zhiwei -- Verschoof, Henry -- Grimwood, Michael -- Dehnhardt, Christoph -- Andrez, Jean-Christophe -- Focken, Thilo -- Sutherlin, Daniel P -- Safina, Brian S -- Starovasnik, Melissa A -- Ortwine, Daniel F -- Franke, Yvonne -- Cohen, Charles J -- Hackos, David H -- Koth, Christopher M -- Payandeh, Jian -- New York, N.Y. -- Science. 2015 Dec 18;350(6267):aac5464. doi: 10.1126/science.aac5464.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural Biology, Genentech Inc., South San Francisco, CA 94080, USA. ; Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA. ; Department of Biology, Xenon Pharmaceuticals Inc., Burnaby, British Columbia, V5G 4W8, Canada. ; Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, USA. ; Department of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA. ; Department of Chemistry, Xenon Pharmaceuticals Inc., Burnaby, British Columbia, V5G 4W8, Canada. ; Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA. hackos.david@gene.com koth.christopher@gene.com payandeh.jian@gene.com. ; Department of Structural Biology, Genentech Inc., South San Francisco, CA 94080, USA. hackos.david@gene.com koth.christopher@gene.com payandeh.jian@gene.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26680203" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cell Membrane/chemistry ; Crystallization/methods ; Crystallography, X-Ray ; DNA Mutational Analysis ; Humans ; Models, Molecular ; Molecular Sequence Data ; NAV1.7 Voltage-Gated Sodium Channel/*chemistry/genetics ; Pain Perception/drug effects ; Protein Engineering ; Protein Isoforms/antagonists & inhibitors/chemistry ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Sodium Channel Blockers/*chemistry/*pharmacology ; Sulfonamides/*chemistry/*pharmacology ; Thiadiazoles/*chemistry/*pharmacology
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  • 49
    Publication Date: 2015-06-13
    Description: The spindle checkpoint of the cell division cycle senses kinetochores that are not attached to microtubules and prevents precocious onset of anaphase, which can lead to aneuploidy. The nuclear division cycle 80 complex (Ndc80C) is a major microtubule receptor at the kinetochore. Ndc80C also mediates the kinetochore recruitment of checkpoint proteins. We found that the checkpoint protein kinase monopolar spindle 1 (Mps1) directly bound to Ndc80C through two independent interactions. Both interactions involved the microtubule-binding surfaces of Ndc80C and were directly inhibited in the presence of microtubules. Elimination of one such interaction in human cells caused checkpoint defects expected from a failure to detect unattached kinetochores. Competition between Mps1 and microtubules for Ndc80C binding thus constitutes a direct mechanism for the detection of unattached kinetochores.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ji, Zhejian -- Gao, Haishan -- Yu, Hongtao -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Jun 12;348(6240):1260-4. doi: 10.1126/science.aaa4029.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 74390, USA. ; Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 74390, USA. hongtao.yu@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26068854" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding, Competitive ; *Cell Cycle ; Cell Cycle Proteins/genetics/*metabolism ; HeLa Cells ; Humans ; Kinetochores/*metabolism ; Microtubules/*metabolism ; Molecular Sequence Data ; Nuclear Proteins/*metabolism ; Protein Binding ; Protein-Serine-Threonine Kinases/genetics/*metabolism ; Protein-Tyrosine Kinases/genetics/*metabolism
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  • 50
    Publication Date: 2015-07-25
    Description: Lipid transfer between cell membrane bilayers at contacts between the endoplasmic reticulum (ER) and other membranes help to maintain membrane lipid homeostasis. We found that two similar ER integral membrane proteins, oxysterol-binding protein (OSBP)-related protein 5 (ORP5) and ORP8, tethered the ER to the plasma membrane (PM) via the interaction of their pleckstrin homology domains with phosphatidylinositol 4-phosphate (PI4P) in this membrane. Their OSBP-related domains (ORDs) harbored either PI4P or phosphatidylserine (PS) and exchanged these lipids between bilayers. Gain- and loss-of-function experiments showed that ORP5 and ORP8 could mediate PI4P/PS countertransport between the ER and the PM, thus delivering PI4P to the ER-localized PI4P phosphatase Sac1 for degradation and PS from the ER to the PM. This exchange helps to control plasma membrane PI4P levels and selectively enrich PS in the PM.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4638224/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4638224/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chung, Jeeyun -- Torta, Federico -- Masai, Kaori -- Lucast, Louise -- Czapla, Heather -- Tanner, Lukas B -- Narayanaswamy, Pradeep -- Wenk, Markus R -- Nakatsu, Fubito -- De Camilli, Pietro -- DA018343/DA/NIDA NIH HHS/ -- DK082700/DK/NIDDK NIH HHS/ -- DK45735/DK/NIDDK NIH HHS/ -- P30 DA018343/DA/NIDA NIH HHS/ -- P30 DK045735/DK/NIDDK NIH HHS/ -- R01 DK082700/DK/NIDDK NIH HHS/ -- R37 NS036251/NS/NINDS NIH HHS/ -- R37NS036251/NS/NINDS NIH HHS/ -- T32 GM007223/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Jul 24;349(6246):428-32. doi: 10.1126/science.aab1370.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Howard Hughes Medical Institute, Kavli Institute for Neuroscience, and Program for Cellular Neuroscience, Neurodegeneration, and Repair, Yale School of Medicine, New Haven, CT 06520, USA. ; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117456 Singapore. ; Department of Cell Biology, Howard Hughes Medical Institute, Kavli Institute for Neuroscience, and Program for Cellular Neuroscience, Neurodegeneration, and Repair, Yale School of Medicine, New Haven, CT 06520, USA. pietro.decamilli@yale.edu nakatsu@med.niigata-u.ac.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26206935" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Biological Transport ; Cell Membrane/*metabolism ; Endoplasmic Reticulum/*metabolism ; Gene Knockout Techniques ; HeLa Cells ; Humans ; Molecular Sequence Data ; Phosphatidylinositol Phosphates/*metabolism ; Phosphatidylserines/*metabolism ; Protein Structure, Tertiary ; Receptors, Steroid/chemistry/genetics/*metabolism
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  • 51
    Publication Date: 2015-03-15
    Description: Rgs2, a regulator of G proteins, lowers blood pressure by decreasing signaling through Galphaq. Human patients expressing Met-Leu-Rgs2 (ML-Rgs2) or Met-Arg-Rgs2 (MR-Rgs2) are hypertensive relative to people expressing wild-type Met-Gln-Rgs2 (MQ-Rgs2). We found that wild-type MQ-Rgs2 and its mutant, MR-Rgs2, were destroyed by the Ac/N-end rule pathway, which recognizes N(alpha)-terminally acetylated (Nt-acetylated) proteins. The shortest-lived mutant, ML-Rgs2, was targeted by both the Ac/N-end rule and Arg/N-end rule pathways. The latter pathway recognizes unacetylated N-terminal residues. Thus, the Nt-acetylated Ac-MX-Rgs2 (X = Arg, Gln, Leu) proteins are specific substrates of the mammalian Ac/N-end rule pathway. Furthermore, the Ac/N-degron of Ac-MQ-Rgs2 was conditional, and Teb4, an endoplasmic reticulum (ER) membrane-embedded ubiquitin ligase, was able to regulate G protein signaling by targeting Ac-MX-Rgs2 proteins for degradation through their N(alpha)-terminal acetyl group.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748709/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748709/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Park, Sang-Eun -- Kim, Jeong-Mok -- Seok, Ok-Hee -- Cho, Hanna -- Wadas, Brandon -- Kim, Seon-Young -- Varshavsky, Alexander -- Hwang, Cheol-Sang -- DK039520/DK/NIDDK NIH HHS/ -- GM031530/GM/NIGMS NIH HHS/ -- R01 DK039520/DK/NIDDK NIH HHS/ -- R01 GM031530/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Mar 13;347(6227):1249-52. doi: 10.1126/science.aaa3844.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, South Korea. ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. ; Medical Genomics Research Center, KRIBB, Daejeon, South Korea. Department of Functional Genomics, University of Science and Technology, Daejeon, South Korea. ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. cshwang@postech.ac.kr avarsh@caltech.edu. ; Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, South Korea. cshwang@postech.ac.kr avarsh@caltech.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25766235" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Amino Acid Sequence ; GTP-Binding Protein alpha Subunits, Gq-G11/metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Membrane Proteins/genetics/metabolism ; Mutant Proteins/chemistry/metabolism ; Protein Processing, Post-Translational ; Protein Stability ; Proteolysis ; RGS Proteins/chemistry/genetics/*metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Signal Transduction ; Ubiquitin-Protein Ligases/genetics/metabolism ; Ubiquitination
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  • 52
    Publication Date: 2015-10-17
    Description: Telomerase helps maintain telomeres by processive synthesis of telomere repeat DNA at their 3'-ends, using an integral telomerase RNA (TER) and telomerase reverse transcriptase (TERT). We report the cryo-electron microscopy structure of Tetrahymena telomerase at ~9 angstrom resolution. In addition to seven known holoenzyme proteins, we identify two additional proteins that form a complex (TEB) with single-stranded telomere DNA-binding protein Teb1, paralogous to heterotrimeric replication protein A (RPA). The p75-p45-p19 subcomplex is identified as another RPA-related complex, CST (CTC1-STN1-TEN1). This study reveals the paths of TER in the TERT-TER-p65 catalytic core and single-stranded DNA exit; extensive subunit interactions of the TERT essential N-terminal domain, p50, and TEB; and other subunit identities and structures, including p19 and p45C crystal structures. Our findings provide structural and mechanistic insights into telomerase holoenzyme function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687456/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687456/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Jiansen -- Chan, Henry -- Cash, Darian D -- Miracco, Edward J -- Ogorzalek Loo, Rachel R -- Upton, Heather E -- Cascio, Duilio -- O'Brien Johnson, Reid -- Collins, Kathleen -- Loo, Joseph A -- Zhou, Z Hong -- Feigon, Juli -- GM007185/GM/NIGMS NIH HHS/ -- GM048123/GM/NIGMS NIH HHS/ -- GM071940/GM/NIGMS NIH HHS/ -- GM101874/GM/NIGMS NIH HHS/ -- GM103479/GM/NIGMS NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- P41 RR015301/RR/NCRR NIH HHS/ -- R01 GM048123/GM/NIGMS NIH HHS/ -- R01 GM054198/GM/NIGMS NIH HHS/ -- R01 GM071940/GM/NIGMS NIH HHS/ -- R01 GM103479/GM/NIGMS NIH HHS/ -- R01GM054198/GM/NIGMS NIH HHS/ -- S10OD018111/OD/NIH HHS/ -- S10RR23057/RR/NCRR NIH HHS/ -- UL1TR000124/TR/NCATS NIH HHS/ -- New York, N.Y. -- Science. 2015 Oct 30;350(6260):aab4070. doi: 10.1126/science.aab4070. Epub 2015 Oct 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Biochemistry, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA 90095, USA. California Nanosystems Institute, UCLA, Los Angeles, CA 90095, USA. ; Department of Chemistry and Biochemistry, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. ; Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA. ; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. ; Department of Chemistry and Biochemistry, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. UCLA-U.S. Department of Energy (DOE) Institute of Genomics and Proteomics, UCLA, Los Angeles, CA 90095, USA. ; Department of Chemistry and Biochemistry, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA. UCLA-U.S. Department of Energy (DOE) Institute of Genomics and Proteomics, UCLA, Los Angeles, CA 90095, USA. ; Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA 90095, USA. California Nanosystems Institute, UCLA, Los Angeles, CA 90095, USA. ; Department of Chemistry and Biochemistry, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. California Nanosystems Institute, UCLA, Los Angeles, CA 90095, USA. UCLA-U.S. Department of Energy (DOE) Institute of Genomics and Proteomics, UCLA, Los Angeles, CA 90095, USA. feigon@mbi.ucla.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26472759" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; Cryoelectron Microscopy ; Crystallography, X-Ray ; DNA, Single-Stranded/chemistry ; Holoenzymes/chemistry ; Protein Binding ; Protein Conformation ; Protein Subunits/chemistry ; RNA/*chemistry ; Replication Protein A/chemistry ; Telomerase/*chemistry ; Telomere/chemistry ; Telomere Homeostasis ; Telomere-Binding Proteins ; Tetrahymena/*enzymology
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  • 53
    Publication Date: 2015-06-27
    Description: Bacterial adaptive immunity uses CRISPR (clustered regularly interspaced short palindromic repeats)-associated (Cas) proteins together with CRISPR transcripts for foreign DNA degradation. In type II CRISPR-Cas systems, activation of Cas9 endonuclease for DNA recognition upon guide RNA binding occurs by an unknown mechanism. Crystal structures of Cas9 bound to single-guide RNA reveal a conformation distinct from both the apo and DNA-bound states, in which the 10-nucleotide RNA "seed" sequence required for initial DNA interrogation is preordered in an A-form conformation. This segment of the guide RNA is essential for Cas9 to form a DNA recognition-competent structure that is poised to engage double-stranded DNA target sequences. We construe this as convergent evolution of a "seed" mechanism reminiscent of that used by Argonaute proteins during RNA interference in eukaryotes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Fuguo -- Zhou, Kaihong -- Ma, Linlin -- Gressel, Saskia -- Doudna, Jennifer A -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Jun 26;348(6242):1477-81. doi: 10.1126/science.aab1452.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. ; Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA. ; Max Planck Institute for Biophysical Chemistry, 37077 Gottingen, Germany. ; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA. California Institute for Quantitative Biosciences, University of California, Berkeley, CA 94720, USA. Department of Chemistry, University of California, Berkeley, CA 94720, USA. Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA. doudna@berkeley.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26113724" target="_blank"〉PubMed〈/a〉
    Keywords: Argonaute Proteins/*chemistry ; Base Sequence ; *CRISPR-Cas Systems ; Caspase 9/*chemistry/genetics ; *Clustered Regularly Interspaced Short Palindromic Repeats ; Crystallography, X-Ray ; DNA/chemistry ; *DNA Cleavage ; Enzyme Activation ; Evolution, Molecular ; Molecular Sequence Data ; Nucleic Acid Conformation ; Protein Structure, Tertiary ; RNA Interference ; RNA, Guide/*chemistry ; Streptococcus pyogenes/*enzymology
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  • 54
    Publication Date: 2015-10-17
    Description: Polycomb repressive complex 2 (PRC2) catalyzes histone H3K27 trimethylation (H3K27me3), a hallmark of gene silencing. Here we report the crystal structures of an active PRC2 complex of 170 kilodaltons from the yeast Chaetomium thermophilum in both basal and stimulated states, which contain Ezh2, Eed, and the VEFS domain of Suz12 and are bound to a cancer-associated inhibiting H3K27M peptide and a S-adenosyl-l-homocysteine cofactor. The stimulated complex also contains an additional stimulating H3K27me3 peptide. Eed is engulfed by a belt-like structure of Ezh2, and Suz12(VEFS) contacts both of these two subunits to confer an unusual split active SET domain for catalysis. Comparison of PRC2 in the basal and stimulated states reveals a mobile Ezh2 motif that responds to stimulation to allosterically regulate the active site.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiao, Lianying -- Liu, Xin -- GM114576/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Oct 16;350(6258):aac4383. doi: 10.1126/science.aac4383. Epub 2015 Oct 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cecil H. and Ida Green Center for Reproductive Biology Sciences and Division of Basic Research, Department of Obstetrics and Gynecology and Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. ; Cecil H. and Ida Green Center for Reproductive Biology Sciences and Division of Basic Research, Department of Obstetrics and Gynecology and Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. xin.liu@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26472914" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Amino Acid Sequence ; Catalysis ; Catalytic Domain ; Chaetomium/genetics/*metabolism ; Crystallography, X-Ray ; Fungal Proteins/antagonists & inhibitors/*chemistry/metabolism ; *Gene Silencing ; Histones/*metabolism ; Humans ; Jumonji Domain-Containing Histone Demethylases/metabolism ; Methylation ; Molecular Sequence Data ; Mutation ; Neoplasms/genetics ; Polycomb Repressive Complex 2/antagonists & inhibitors/*chemistry/metabolism ; Protein Structure, Tertiary ; S-Adenosylhomocysteine/chemistry/metabolism ; Transcription, Genetic
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  • 55
    Publication Date: 2015-06-27
    Description: Algal blooms produce large amounts of dimethyl sulfide (DMS), a volatile with a diverse signaling role in marine food webs that is emitted to the atmosphere, where it can affect cloud formation. The algal enzymes responsible for forming DMS from dimethylsulfoniopropionate (DMSP) remain unidentified despite their critical role in the global sulfur cycle. We identified and characterized Alma1, a DMSP lyase from the bloom-forming algae Emiliania huxleyi. Alma1 is a tetrameric, redox-sensitive enzyme of the aspartate racemase superfamily. Recombinant Alma1 exhibits biochemical features identical to the DMSP lyase in E. huxleyi, and DMS released by various E. huxleyi isolates correlates with their Alma1 levels. Sequence homology searches suggest that Alma1 represents a gene family present in major, globally distributed phytoplankton taxa and in other marine organisms.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Alcolombri, Uria -- Ben-Dor, Shifra -- Feldmesser, Ester -- Levin, Yishai -- Tawfik, Dan S -- Vardi, Assaf -- New York, N.Y. -- Science. 2015 Jun 26;348(6242):1466-9. doi: 10.1126/science.aab1586.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel. Department of Plant and Environmental Sciences, Weizmann Institute of Science, Rehovot 76100, Israel. ; Bioinformatics and Biological Computing Unit, Biological Services, Weizmann Institute of Science, Rehovot 76100, Israel. ; Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 76100, Israel. ; Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel. assaf.vardi@weizmann.ac.il dan.tawfik@weizmann.ac.il. ; Department of Plant and Environmental Sciences, Weizmann Institute of Science, Rehovot 76100, Israel. assaf.vardi@weizmann.ac.il dan.tawfik@weizmann.ac.il.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26113722" target="_blank"〉PubMed〈/a〉
    Keywords: Algal Proteins/*chemistry/classification/genetics ; Amino Acid Sequence ; Bacteria/enzymology/genetics ; Carbon-Sulfur Lyases/*chemistry/classification/genetics ; Haptophyta/*enzymology/genetics ; Molecular Sequence Data ; Phylogeny ; Phytoplankton/enzymology ; RNA, Messenger/biosynthesis ; Recombinant Proteins/chemistry ; Sulfides/*metabolism
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  • 56
    Publication Date: 2015-09-26
    Description: Mitochondria fulfill central functions in cellular energetics, metabolism, and signaling. The outer membrane translocator complex (the TOM complex) imports most mitochondrial proteins, but its architecture is unknown. Using a cross-linking approach, we mapped the active translocator down to single amino acid residues, revealing different transport paths for preproteins through the Tom40 channel. An N-terminal segment of Tom40 passes from the cytosol through the channel to recruit chaperones from the intermembrane space that guide the transfer of hydrophobic preproteins. The translocator contains three Tom40 beta-barrel channels sandwiched between a central alpha-helical Tom22 receptor cluster and external regulatory Tom proteins. The preprotein-translocating trimeric complex exchanges with a dimeric isoform to assemble new TOM complexes. Dynamic coupling of alpha-helical receptors, beta-barrel channels, and chaperones generates a versatile machinery that transports about 1000 different proteins.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shiota, Takuya -- Imai, Kenichiro -- Qiu, Jian -- Hewitt, Victoria L -- Tan, Khershing -- Shen, Hsin-Hui -- Sakiyama, Noriyuki -- Fukasawa, Yoshinori -- Hayat, Sikander -- Kamiya, Megumi -- Elofsson, Arne -- Tomii, Kentaro -- Horton, Paul -- Wiedemann, Nils -- Pfanner, Nikolaus -- Lithgow, Trevor -- Endo, Toshiya -- New York, N.Y. -- Science. 2015 Sep 25;349(6255):1544-8. doi: 10.1126/science.aac6428.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Victoria 3800, Australia. Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan. ; Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan. ; Institut fur Biochemie und Molekularbiologie, Universitat Freiburg, 79104 Freiburg, Germany. ; Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Victoria 3800, Australia. ; Department of Biochemistry and Biophysics and Science for Life Laboratory, Stockholm University, Box 1031, 17121 Solna, Sweden. ; Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan. ; Institut fur Biochemie und Molekularbiologie, Universitat Freiburg, 79104 Freiburg, Germany. Centre for Biological Signalling Studies, Universitat Freiburg, 79104 Freiburg, Germany. ; Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan. Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-motoyama, Kita-ku, Kyoto 603-8555, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26404837" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cytosol/metabolism ; Mitochondrial Membrane Transport Proteins/*chemistry/metabolism ; Molecular Chaperones ; Molecular Sequence Data ; Protein Multimerization ; Protein Structure, Secondary ; Protein Transport ; Saccharomyces cerevisiae Proteins/*chemistry/metabolism
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  • 57
    Publication Date: 2015-02-24
    Description: The fleeting lifetimes of the transition states (TSs) of chemical reactions make determination of their three-dimensional structures by diffraction methods a challenge. Here, we used packing interactions within the core of a protein to stabilize the planar TS conformation for rotation around the central carbon-carbon bond of biphenyl so that it could be directly observed by x-ray crystallography. The computational protein design software Rosetta was used to design a pocket within threonyl-transfer RNA synthetase from the thermophile Pyrococcus abyssi that forms complementary van der Waals interactions with a planar biphenyl. This latter moiety was introduced biosynthetically as the side chain of the noncanonical amino acid p-biphenylalanine. Through iterative rounds of computational design and structural analysis, we identified a protein in which the side chain of p-biphenylalanine is trapped in the energetically disfavored, coplanar conformation of the TS of the bond rotation reaction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581533/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581533/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pearson, Aaron D -- Mills, Jeremy H -- Song, Yifan -- Nasertorabi, Fariborz -- Han, Gye Won -- Baker, David -- Stevens, Raymond C -- Schultz, Peter G -- 2 R01 GM097206-05/GM/NIGMS NIH HHS/ -- F32 GM099210/GM/NIGMS NIH HHS/ -- F32GM099210/GM/NIGMS NIH HHS/ -- R01 GM097206/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Feb 20;347(6224):863-7. doi: 10.1126/science.aaa2424.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. ; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. ; Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA. ; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Howard Hughes Medical Institute (HHMI), University of Washington, Seattle, WA 98195, USA. ; Department of Chemistry and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. schultz@scripps.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25700516" target="_blank"〉PubMed〈/a〉
    Keywords: Alanine/*analogs & derivatives/chemistry ; Archaeal Proteins/*chemistry ; Biphenyl Compounds/*chemistry ; Computer Simulation ; Computer-Aided Design ; Crystallography, X-Ray ; Entropy ; Models, Chemical ; Protein Structure, Secondary ; Pyrococcus abyssi/*enzymology ; Software ; Threonine-tRNA Ligase/*chemistry
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  • 58
    Publication Date: 2015-02-24
    Description: Notch receptors guide mammalian cell fate decisions by engaging the proteins Jagged and Delta-like (DLL). The 2.3 angstrom resolution crystal structure of the interacting regions of the Notch1-DLL4 complex reveals a two-site, antiparallel binding orientation assisted by Notch1 O-linked glycosylation. Notch1 epidermal growth factor-like repeats 11 and 12 interact with the DLL4 Delta/Serrate/Lag-2 (DSL) domain and module at the N-terminus of Notch ligands (MNNL) domains, respectively. Threonine and serine residues on Notch1 are functionalized with O-fucose and O-glucose, which act as surrogate amino acids by making specific, and essential, contacts to residues on DLL4. The elucidation of a direct chemical role for O-glycans in Notch1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites, Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445638/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445638/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Luca, Vincent C -- Jude, Kevin M -- Pierce, Nathan W -- Nachury, Maxence V -- Fischer, Suzanne -- Garcia, K Christopher -- 1R01-GM097015/GM/NIGMS NIH HHS/ -- R01 GM097015/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Feb 20;347(6224):847-53. doi: 10.1126/science.1261093.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. kcgarcia@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25700513" target="_blank"〉PubMed〈/a〉
    Keywords: Alagille Syndrome/genetics ; Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Cell Line ; Conserved Sequence ; Crystallography, X-Ray ; Fucose/chemistry ; Glucose/chemistry ; Glycosylation ; Intracellular Signaling Peptides and Proteins/*chemistry/genetics ; Ligands ; Membrane Proteins/*chemistry/genetics/ultrastructure ; Molecular Sequence Data ; Molecular Targeted Therapy ; Polysaccharides/chemistry ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics ; Protein Binding ; Protein Structure, Tertiary ; Rats ; Receptor, Notch1/*chemistry/genetics/ultrastructure ; Serine/chemistry/genetics ; Threonine/chemistry/genetics
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  • 59
    Publication Date: 2015-04-04
    Description: The highly divergent ribosomes of human mitochondria (mitoribosomes) synthesize 13 essential proteins of oxidative phosphorylation complexes. We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by means of single-particle electron cryogenic microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three ribosomal RNA molecules. The head domain of the small subunit, particularly the messenger (mRNA) channel, is highly remodeled. Many intersubunit bridges are specific to the mitoribosome, which adopts conformations involving ratcheting or rolling of the small subunit that are distinct from those seen in bacteria or eukaryotes. An intrinsic guanosine triphosphatase mediates a contact between the head and central protuberance. The structure provides a reference for analysis of mutations that cause severe pathologies and for future drug design.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501431/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501431/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Amunts, Alexey -- Brown, Alan -- Toots, Jaan -- Scheres, Sjors H W -- Ramakrishnan, V -- 096570/Wellcome Trust/United Kingdom -- MC_U105184332/Medical Research Council/United Kingdom -- MC_UP_A025_1013/Medical Research Council/United Kingdom -- WT096570/Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2015 Apr 3;348(6230):95-8. doi: 10.1126/science.aaa1193. Epub 2015 Apr 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council (MRC) Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. ; Medical Research Council (MRC) Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. ramak@mrc-lmb.cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25838379" target="_blank"〉PubMed〈/a〉
    Keywords: Aminoglycosides/pharmacology/therapeutic use ; Anti-Bacterial Agents/pharmacology ; Crystallography, X-Ray ; Drug Resistance, Bacterial/genetics ; GTP Phosphohydrolases/chemistry ; Genetic Diseases, Inborn/drug therapy/genetics ; Humans ; Mitochondria/chemistry/*ultrastructure ; RNA, Messenger/chemistry ; RNA, Ribosomal/chemistry ; Ribosomal Proteins/chemistry ; Ribosomes/chemistry/genetics/*ultrastructure
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  • 60
    Publication Date: 2015-05-23
    Description: The development of effective pharmacological inhibitors of multidomain scaffold proteins, notably transcription factors, is a particularly challenging problem. In part, this is because many small-molecule antagonists disrupt the activity of only one domain in the target protein. We devised a chemical strategy that promotes ligand-dependent target protein degradation using as an example the transcriptional coactivator BRD4, a protein critical for cancer cell growth and survival. We appended a competitive antagonist of BET bromodomains to a phthalimide moiety to hijack the cereblon E3 ubiquitin ligase complex. The resultant compound, dBET1, induced highly selective cereblon-dependent BET protein degradation in vitro and in vivo and delayed leukemia progression in mice. A second series of probes resulted in selective degradation of the cytosolic protein FKBP12. This chemical strategy for controlling target protein stability may have implications for therapeutically targeting previously intractable proteins.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Winter, Georg E -- Buckley, Dennis L -- Paulk, Joshiawa -- Roberts, Justin M -- Souza, Amanda -- Dhe-Paganon, Sirano -- Bradner, James E -- P01 CA066996/CA/NCI NIH HHS/ -- P01-CA066996/CA/NCI NIH HHS/ -- R01-CA176745/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 19;348(6241):1376-81. doi: 10.1126/science.aab1433. Epub 2015 May 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. ; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. james_bradner@dfci.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25999370" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Azepines/chemistry/*pharmacology/therapeutic use ; Cell Line, Tumor ; Crystallography, X-Ray ; Disease Models, Animal ; *Drug Design ; Leukemia, Promyelocytic, Acute/drug therapy ; Ligands ; Mice ; Molecular Targeted Therapy ; Nuclear Proteins/antagonists & inhibitors/chemistry/*metabolism ; Peptide Hydrolases/*metabolism ; Phthalimides/*chemistry ; Protein Stability/drug effects ; Protein Structure, Tertiary ; Proteolysis/*drug effects ; Tacrolimus Binding Protein 1A/metabolism ; Thalidomide/*analogs & derivatives/chemistry/pharmacology/therapeutic use ; Transcription Factors/antagonists & inhibitors/chemistry/*metabolism ; Ubiquitin-Protein Ligases/metabolism
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  • 61
    Publication Date: 2015-06-27
    Description: Morphinan alkaloids from the opium poppy are used for pain relief. The direction of metabolites to morphinan biosynthesis requires isomerization of (S)- to (R)-reticuline. Characterization of high-reticuline poppy mutants revealed a genetic locus, designated STORR [(S)- to (R)-reticuline] that encodes both cytochrome P450 and oxidoreductase modules, the latter belonging to the aldo-keto reductase family. Metabolite analysis of mutant alleles and heterologous expression demonstrate that the P450 module is responsible for the conversion of (S)-reticuline to 1,2-dehydroreticuline, whereas the oxidoreductase module converts 1,2-dehydroreticuline to (R)-reticuline rather than functioning as a P450 redox partner. Proteomic analysis confirmed that these two modules are contained on a single polypeptide in vivo. This modular assembly implies a selection pressure favoring substrate channeling. The fusion protein STORR may enable microbial-based morphinan production.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Winzer, Thilo -- Kern, Marcelo -- King, Andrew J -- Larson, Tony R -- Teodor, Roxana I -- Donninger, Samantha L -- Li, Yi -- Dowle, Adam A -- Cartwright, Jared -- Bates, Rachel -- Ashford, David -- Thomas, Jerry -- Walker, Carol -- Bowser, Tim A -- Graham, Ian A -- BB/K018809/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Jul 17;349(6245):309-12. doi: 10.1126/science.aab1852. Epub 2015 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Novel Agricultural Products, Department of Biology, University of York, York YO10 5DD, UK. ; Bioscience Technology Facility, Department of Biology, University of York, York YO10 5DD, UK. ; GlaxoSmithKline, 1061 Mountain Highway, Post Office Box 168, Boronia, Victoria 3155, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26113639" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Benzylisoquinolines/chemistry/*metabolism ; Cytochrome P-450 Enzyme System/genetics/*metabolism ; Genetic Loci ; Isoquinolines/chemistry/*metabolism ; Molecular Sequence Data ; Morphinans/chemistry/*metabolism ; Mutation ; Oxidation-Reduction ; Papaver/*enzymology/genetics ; Plant Proteins/genetics/*metabolism ; Quaternary Ammonium Compounds/chemistry/*metabolism
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  • 62
    Publication Date: 2015-02-24
    Description: Navigation depends on multiple neural systems that encode the moment-to-moment changes in an animal's direction and location in space. These include head direction (HD) cells representing the orientation of the head and grid cells that fire at multiple locations, forming a repeating hexagonal grid pattern. Computational models hypothesize that generation of the grid cell signal relies upon HD information that ascends to the hippocampal network via the anterior thalamic nuclei (ATN). We inactivated or lesioned the ATN and subsequently recorded single units in the entorhinal cortex and parasubiculum. ATN manipulation significantly disrupted grid and HD cell characteristics while sparing theta rhythmicity in these regions. These results indicate that the HD signal via the ATN is necessary for the generation and function of grid cell activity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476794/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476794/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Winter, Shawn S -- Clark, Benjamin J -- Taube, Jeffrey S -- NS053907/NS/NINDS NIH HHS/ -- R01 MH048924/MH/NIMH NIH HHS/ -- R01 NS053907/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2015 Feb 20;347(6224):870-4. doi: 10.1126/science.1259591. Epub 2015 Feb 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Psychological and Brain Sciences, Center for Cognitive Neuroscience, Dartmouth College, Hanover, NH 03755, USA. ; Department of Psychological and Brain Sciences, Center for Cognitive Neuroscience, Dartmouth College, Hanover, NH 03755, USA. jeffrey.taube@dartmouth.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25700518" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anterior Thalamic Nuclei/drug effects/*physiology ; Entorhinal Cortex/cytology/*physiology ; Female ; Head ; Hippocampus/cytology/physiology ; Lidocaine/pharmacology ; Nerve Net/cytology/drug effects/*physiology ; Neurons/*physiology ; Orientation/*physiology ; Rats ; Rats, Inbred LEC ; Signal Transduction ; Spatial Navigation/*physiology ; Theta Rhythm
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  • 63
    Publication Date: 2015-02-14
    Description: Nucleotide analog inhibitors have shown clinical success in the treatment of hepatitis C virus (HCV) infection, despite an incomplete mechanistic understanding of NS5B, the viral RNA-dependent RNA polymerase. Here we study the details of HCV RNA replication by determining crystal structures of stalled polymerase ternary complexes with enzymes, RNA templates, RNA primers, incoming nucleotides, and catalytic metal ions during both primed initiation and elongation of RNA synthesis. Our analysis revealed that highly conserved active-site residues in NS5B position the primer for in-line attack on the incoming nucleotide. A beta loop and a C-terminal membrane-anchoring linker occlude the active-site cavity in the apo state, retract in the primed initiation assembly to enforce replication of the HCV genome from the 3' terminus, and vacate the active-site cavity during elongation. We investigated the incorporation of nucleotide analog inhibitors, including the clinically active metabolite formed by sofosbuvir, to elucidate key molecular interactions in the active site.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Appleby, Todd C -- Perry, Jason K -- Murakami, Eisuke -- Barauskas, Ona -- Feng, Joy -- Cho, Aesop -- Fox, David 3rd -- Wetmore, Diana R -- McGrath, Mary E -- Ray, Adrian S -- Sofia, Michael J -- Swaminathan, S -- Edwards, Thomas E -- New York, N.Y. -- Science. 2015 Feb 13;347(6223):771-5. doi: 10.1126/science.1259210.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA. todd.appleby@gilead.com tedwards@be4.com. ; Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA. ; Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA. ; Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA. todd.appleby@gilead.com tedwards@be4.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25678663" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Catalytic Domain ; Conserved Sequence ; Crystallography, X-Ray ; Hepacivirus/enzymology/genetics/*physiology ; Molecular Sequence Data ; Protein Structure, Secondary ; RNA Replicase/*chemistry ; RNA, Viral/*biosynthesis ; Ribonucleotides/*chemistry ; Sofosbuvir ; Uridine Monophosphate/analogs & derivatives/chemistry ; Viral Nonstructural Proteins/*chemistry ; *Virus Replication
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  • 64
    Publication Date: 2015-11-07
    Description: Anion exchanger 1 (AE1), also known as band 3 or SLC4A1, plays a key role in the removal of carbon dioxide from tissues by facilitating the exchange of chloride and bicarbonate across the plasma membrane of erythrocytes. An isoform of AE1 is also present in the kidney. Specific mutations in human AE1 cause several types of hereditary hemolytic anemias and/or distal renal tubular acidosis. Here we report the crystal structure of the band 3 anion exchanger domain (AE1(CTD)) at 3.5 angstroms. The structure is locked in an outward-facing open conformation by an inhibitor. Comparing this structure with a substrate-bound structure of the uracil transporter UraA in an inward-facing conformation allowed us to identify the anion-binding position in the AE1(CTD), and to propose a possible transport mechanism that could explain why selected mutations lead to disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arakawa, Takatoshi -- Kobayashi-Yurugi, Takami -- Alguel, Yilmaz -- Iwanari, Hiroko -- Hatae, Hinako -- Iwata, Momi -- Abe, Yoshito -- Hino, Tomoya -- Ikeda-Suno, Chiyo -- Kuma, Hiroyuki -- Kang, Dongchon -- Murata, Takeshi -- Hamakubo, Takao -- Cameron, Alexander D -- Kobayashi, Takuya -- Hamasaki, Naotaka -- Iwata, So -- BB/D019516/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/G023425/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- WT089809/Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2015 Nov 6;350(6261):680-4. doi: 10.1126/science.aaa4335.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. JST, Research Acceleration Program, Membrane Protein Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Cell Biology, Kyoto University Faculty of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. ; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Cell Biology, Kyoto University Faculty of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. ; Division of Molecular Biosciences, Membrane Protein Crystallography group, Imperial College London, London SW7 2AZ, UK. Membrane Protein Laboratory, Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Chilton, Oxfordshire OX11 0DE, UK. Research Complex at Harwell Rutherford, Appleton Laboratory, Harwell Oxford, Didcot, Oxfordshire OX11 0FA, UK. ; Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan. ; Faculty of Pharmaceutical Sciences, Nagasaki International University, 2825-7 Huis Ten Bosch-cho, Sasebo, Nagasaki 859-3298, Japan. ; Division of Molecular Biosciences, Membrane Protein Crystallography group, Imperial College London, London SW7 2AZ, UK. Membrane Protein Laboratory, Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Chilton, Oxfordshire OX11 0DE, UK. ; Department of Protein Structure, Function and Design, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. ; Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. ; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Cell Biology, Kyoto University Faculty of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage, Chiba 263-8522, Japan. ; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Division of Molecular Biosciences, Membrane Protein Crystallography group, Imperial College London, London SW7 2AZ, UK. Membrane Protein Laboratory, Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Chilton, Oxfordshire OX11 0DE, UK. Research Complex at Harwell Rutherford, Appleton Laboratory, Harwell Oxford, Didcot, Oxfordshire OX11 0FA, UK. School of Life Sciences, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK. ; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. JST, Research Acceleration Program, Membrane Protein Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Cell Biology, Kyoto University Faculty of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Platform for Drug Discovery, Informatics, and Structural Life Science, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. ; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. JST, Research Acceleration Program, Membrane Protein Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Cell Biology, Kyoto University Faculty of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Division of Molecular Biosciences, Membrane Protein Crystallography group, Imperial College London, London SW7 2AZ, UK. Membrane Protein Laboratory, Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Chilton, Oxfordshire OX11 0DE, UK. Research Complex at Harwell Rutherford, Appleton Laboratory, Harwell Oxford, Didcot, Oxfordshire OX11 0FA, UK. Platform for Drug Discovery, Informatics, and Structural Life Science, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26542571" target="_blank"〉PubMed〈/a〉
    Keywords: Anion Exchange Protein 1, Erythrocyte/*chemistry/genetics ; Crystallography, X-Ray ; Disease/genetics ; Escherichia coli Proteins/chemistry ; Humans ; Membrane Transport Proteins/chemistry ; Mutation ; Protein Structure, Secondary ; Protein Structure, Tertiary
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  • 65
    Publication Date: 2015-07-04
    Description: The scent of roses (Rosa x hybrida) is composed of hundreds of volatile molecules. Monoterpenes represent up to 70% percent of the scent content in some cultivars, such as the Papa Meilland rose. Monoterpene biosynthesis in plants relies on plastid-localized terpene synthases. Combining transcriptomic and genetic approaches, we show that the Nudix hydrolase RhNUDX1, localized in the cytoplasm, is part of a pathway for the biosynthesis of free monoterpene alcohols that contribute to fragrance in roses. The RhNUDX1 protein shows geranyl diphosphate diphosphohydrolase activity in vitro and supports geraniol biosynthesis in planta.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Magnard, Jean-Louis -- Roccia, Aymeric -- Caissard, Jean-Claude -- Vergne, Philippe -- Sun, Pulu -- Hecquet, Romain -- Dubois, Annick -- Hibrand-Saint Oyant, Laurence -- Jullien, Frederic -- Nicole, Florence -- Raymond, Olivier -- Huguet, Stephanie -- Baltenweck, Raymonde -- Meyer, Sophie -- Claudel, Patricia -- Jeauffre, Julien -- Rohmer, Michel -- Foucher, Fabrice -- Hugueney, Philippe -- Bendahmane, Mohammed -- Baudino, Sylvie -- New York, N.Y. -- Science. 2015 Jul 3;349(6243):81-3. doi: 10.1126/science.aab0696.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratoire BVpam, EA3061, Universite de Lyon/Saint-Etienne, 23 Rue du Dr Michelon, F-42000, Saint-Etienne, France. ; Laboratoire BVpam, EA3061, Universite de Lyon/Saint-Etienne, 23 Rue du Dr Michelon, F-42000, Saint-Etienne, France. Laboratoire Reproduction et Developpement des Plantes UMR Institut National de la Recherche Agronomique (INRA)-CNRS, Universite Lyon 1-ENSL, Ecole Normale Superieure de Lyon, 46 Allee d'Italie, 69364 Lyon Cedex 07, France. ; Laboratoire Reproduction et Developpement des Plantes UMR Institut National de la Recherche Agronomique (INRA)-CNRS, Universite Lyon 1-ENSL, Ecole Normale Superieure de Lyon, 46 Allee d'Italie, 69364 Lyon Cedex 07, France. ; INRA, Institut de Recherche en Horticulture et Semences (INRA, AGROCAMPUS-OUEST, Universite d'Angers), SFR 4207 QUASAV, BP 60057, 49071 Beaucouze Cedex, France. ; Genomiques Fonctionnelles d'Arabidopsis, Unite de Recherche en Genomique Vegetale, UMR INRA 1165-Universite d'Evry Val d'Essonne-ERL CNRS 8196, Evry, France. ; INRA, Universite de Strasbourg, UMR 1131 Sante de la Vigne et Qualite du Vin, 28 Rue de Herrlisheim, F-68000 Colmar, France. ; Universite de Strasbourg-CNRS, UMR 7177, Institut Le Bel, 4 Rue Blaise Pascal, 67070 Strasbourg Cedex, France. ; INRA, Universite de Strasbourg, UMR 1131 Sante de la Vigne et Qualite du Vin, 28 Rue de Herrlisheim, F-68000 Colmar, France. sylvie.baudino@univ-st-etienne.fr philippe.hugueney@colmar.inra.fr mohammed.bendahmane@ens-lyon.fr. ; Laboratoire Reproduction et Developpement des Plantes UMR Institut National de la Recherche Agronomique (INRA)-CNRS, Universite Lyon 1-ENSL, Ecole Normale Superieure de Lyon, 46 Allee d'Italie, 69364 Lyon Cedex 07, France. sylvie.baudino@univ-st-etienne.fr philippe.hugueney@colmar.inra.fr mohammed.bendahmane@ens-lyon.fr. ; Laboratoire BVpam, EA3061, Universite de Lyon/Saint-Etienne, 23 Rue du Dr Michelon, F-42000, Saint-Etienne, France. sylvie.baudino@univ-st-etienne.fr philippe.hugueney@colmar.inra.fr mohammed.bendahmane@ens-lyon.fr.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26138978" target="_blank"〉PubMed〈/a〉
    Keywords: Molecular Sequence Data ; Monoterpenes/*metabolism ; *Odors ; Plastids/*enzymology ; Pyrophosphatases/*biosynthesis/genetics ; Rosa/*enzymology/genetics ; Terpenes/*metabolism ; Transcriptome ; Volatile Organic Compounds/*metabolism
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  • 66
    Publication Date: 2015-11-14
    Description: In healthy individuals, the intestinal microbiota cannot access the liver, spleen, or other peripheral tissues. Some pathogenic bacteria can reach these sites, however, and can induce a systemic immune response. How such compartmentalization is achieved is unknown. We identify a gut-vascular barrier (GVB) in mice and humans that controls the translocation of antigens into the blood stream and prohibits entry of the microbiota. Salmonella typhimurium can penetrate the GVB in a manner dependent on its pathogenicity island (Spi) 2-encoded type III secretion system and on decreased beta-catenin-dependent signaling in gut endothelial cells. The GVB is modified in celiac disease patients with elevated serum transaminases, which indicates that GVB dismantling may be responsible for liver damage in these patients. Understanding the GVB may provide new insights into the regulation of the gut-liver axis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Spadoni, Ilaria -- Zagato, Elena -- Bertocchi, Alice -- Paolinelli, Roberta -- Hot, Edina -- Di Sabatino, Antonio -- Caprioli, Flavio -- Bottiglieri, Luca -- Oldani, Amanda -- Viale, Giuseppe -- Penna, Giuseppe -- Dejana, Elisabetta -- Rescigno, Maria -- New York, N.Y. -- Science. 2015 Nov 13;350(6262):830-4. doi: 10.1126/science.aad0135.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. ; The Italian Foundation for Cancer Research (FIRC) Institute of Molecular Oncology (IFOM), Milan, Italy. ; First Department of Medicine, St. Matteo Hospital, University of Pavia, Pavia, Italy. ; Unita Operativa Gastroenterologia ed Endoscopia, Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico di Milano, and Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Universita degli Studi di Milano, Milan, Italy. ; Department of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy. ; The Italian Foundation for Cancer Research (FIRC) Institute of Molecular Oncology (IFOM), Milan, Italy. Department of Biosciences, Universita degli Studi di Milano, Italy. Department of Genetics, Immunology and Pathology, Uppsala University, Uppsala, Sweden. ; Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. Department of Biosciences, Universita degli Studi di Milano, Italy. maria.rescigno@ieo.eu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26564856" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Bacterial/blood/immunology ; Capillary Permeability/*immunology ; Celiac Disease/blood/immunology/microbiology ; Genomic Islands/genetics/immunology ; Humans ; Ileum/blood supply/immunology/microbiology ; Intestinal Mucosa/immunology/microbiology ; Intestines/blood supply/*immunology/*microbiology ; Liver/immunology ; Mice ; Mice, Inbred C57BL ; Microbiota/*immunology ; Salmonella Infections/*immunology ; Salmonella typhimurium/genetics/*immunology/pathogenicity ; Signal Transduction ; Spleen/immunology ; Transaminases/blood ; Type III Secretion Systems/genetics/immunology ; Wnt Signaling Pathway ; beta Catenin/metabolism
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  • 67
    Publication Date: 2015-04-18
    Description: Conformational control of biomolecular activities can reveal functional insights and enable the engineering of novel activities. Here we show that conformational control through intramolecular cross-linking of a helicase monomer with undetectable unwinding activity converts it into a superhelicase that can unwind thousands of base pairs processively, even against a large opposing force. A natural partner that enhances the helicase activity is shown to achieve its stimulating role also by selectively stabilizing the active conformation. Our work provides insight into the regulation of nucleic acid unwinding activity and introduces a monomeric superhelicase without nuclease activities, which may be useful for biotechnological applications.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417355/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417355/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arslan, Sinan -- Khafizov, Rustem -- Thomas, Christopher D -- Chemla, Yann R -- Ha, Taekjip -- GM065367/GM/NIGMS NIH HHS/ -- R01 GM065367/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Apr 17;348(6232):344-7. doi: 10.1126/science.aaa0445.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Physics Department and Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. ; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK. ; Physics Department and Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Howard Hughes Medical Institute, University of Illinois, Urbana, IL 61801, USA. tjha@illinois.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25883358" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/genetics ; Cross-Linking Reagents/chemistry ; Crystallography, X-Ray ; DNA Helicases/*chemistry/genetics ; *DNA Replication ; DNA, Single-Stranded/*chemistry ; Deoxyribonucleases/chemistry/genetics ; Enzyme Stability ; Escherichia coli Proteins/*chemistry/genetics ; Protein Conformation ; Protein Engineering
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  • 68
    Publication Date: 2015-12-19
    Description: The voltage-gated calcium channel Ca(v)1.1 is engaged in the excitation-contraction coupling of skeletal muscles. The Ca(v)1.1 complex consists of the pore-forming subunit alpha1 and auxiliary subunits alpha2delta, beta, and gamma. We report the structure of the rabbit Ca(v)1.1 complex determined by single-particle cryo-electron microscopy. The four homologous repeats of the alpha1 subunit are arranged clockwise in the extracellular view. The gamma subunit, whose structure resembles claudins, interacts with the voltage-sensing domain of repeat IV (VSD(IV)), whereas the cytosolic beta subunit is located adjacent to VSD(II) of alpha1. The alpha2 subunit interacts with the extracellular loops of repeats I to III through its VWA and Cache1 domains. The structure reveals the architecture of a prototypical eukaryotic Ca(v) channel and provides a framework for understanding the function and disease mechanisms of Ca(v) and Na(v) channels.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Jianping -- Yan, Zhen -- Li, Zhangqiang -- Yan, Chuangye -- Lu, Shan -- Dong, Mengqiu -- Yan, Nieng -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Dec 18;350(6267):aad2395. doi: 10.1126/science.aad2395.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China. Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China. Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. ; National Institute of Biological Sciences, Beijing 102206, China. ; State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China. Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China. Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. nyan@tsinghua.edu.cn.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26680202" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Calcium Channels, L-Type/*chemistry/genetics/isolation & purification ; Cell Membrane/chemistry ; Cryoelectron Microscopy ; Molecular Sequence Data ; Muscle, Skeletal/chemistry ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Protein Subunits/isolation & purification ; Rabbits
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  • 69
    Publication Date: 2015-12-19
    Description: Speciation, the process by which new biological species arise, involves the evolution of reproductive barriers, such as hybrid sterility or inviability between populations. However, identifying hybrid incompatibility genes remains a key obstacle in understanding the molecular basis of reproductive isolation. We devised a genomic screen, which identified a cell cycle-regulation gene as the cause of male inviability in hybrids resulting from a cross between Drosophila melanogaster and D. simulans. Ablation of the D. simulans allele of this gene is sufficient to rescue the adult viability of hybrid males. This dominantly acting cell cycle regulator causes mitotic arrest and, thereby, inviability of male hybrid larvae. Our genomic method provides a facile means to accelerate the identification of hybrid incompatibility genes in other model and nonmodel systems.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703311/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703311/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Phadnis, Nitin -- Baker, EmilyClare P -- Cooper, Jacob C -- Frizzell, Kimberly A -- Hsieh, Emily -- de la Cruz, Aida Flor A -- Shendure, Jay -- Kitzman, Jacob O -- Malik, Harmit S -- 5T32 HD0741/HD/NICHD NIH HHS/ -- HG006283/HG/NHGRI NIH HHS/ -- R01 GM074108/GM/NIGMS NIH HHS/ -- R01 GM115914/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Dec 18;350(6267):1552-5. doi: 10.1126/science.aac7504.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, University of Utah, Salt Lake City, UT 84112, USA. nitin.phadnis@utah.edu hsmalik@fhcrc.org. ; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. ; Department of Biology, University of Utah, Salt Lake City, UT 84112, USA. ; Genome Sciences, University of Washington, Seattle, WA 98195, USA. Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. ; Genome Sciences, University of Washington, Seattle, WA 98195, USA. Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA. ; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. nitin.phadnis@utah.edu hsmalik@fhcrc.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26680200" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Carrier Proteins/genetics/*physiology ; Cell Cycle/*genetics ; Chimera/genetics ; Crosses, Genetic ; Drosophila melanogaster/*genetics/growth & development ; Drosophila simulans/*genetics/growth & development ; Gene Expression Regulation, Developmental ; Genes, Essential/genetics/physiology ; Genes, Insect ; Genes, Lethal/genetics/*physiology ; *Genetic Speciation ; Male ; Molecular Sequence Data ; *Reproductive Isolation
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  • 70
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2015-10-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cohen, Jeremiah Y -- New York, N.Y. -- Science. 2015 Oct 2;350(6256):47. doi: 10.1126/science.aad3003.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Solomon H. Snyder Department of Neuroscience, Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. jeremiah.cohen@jhmi.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26430113" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/*physiology ; Dopamine/*metabolism ; Dopaminergic Neurons/*metabolism ; Electric Stimulation ; Humans ; Mice ; Neurophysiology/trends ; *Reward ; Serotonin/*metabolism ; Signal Transduction ; Time Factors ; Ventral Tegmental Area/*cytology
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  • 71
    Publication Date: 2015-08-22
    Description: Many transcriptional activators act at a distance from core promoter elements and work by recruiting RNA polymerase through protein-protein interactions. We show here how the prokaryotic regulatory protein CueR both represses and activates transcription by differentially modulating local DNA structure within the promoter. Structural studies reveal that the repressor state slightly bends the promoter DNA, precluding optimal RNA polymerase-promoter recognition. Upon binding a metal ion in the allosteric site, CueR switches into an activator conformation. It maintains all protein-DNA contacts but introduces torsional stresses that kink and undertwist the promoter, stabilizing an A-form DNA-like conformation. These factors switch on and off transcription by exerting dynamic control of DNA stereochemistry, reshaping the core promoter and making it a better or worse substrate for polymerase.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617686/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617686/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Philips, Steven J -- Canalizo-Hernandez, Monica -- Yildirim, Ilyas -- Schatz, George C -- Mondragon, Alfonso -- O'Halloran, Thomas V -- R01 GM038784/GM/NIGMS NIH HHS/ -- R01GM038784/GM/NIGMS NIH HHS/ -- U54 CA143869/CA/NCI NIH HHS/ -- U54 CA193419/CA/NCI NIH HHS/ -- U54CA143869/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2015 Aug 21;349(6250):877-81. doi: 10.1126/science.aaa9809.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA. ; Department of Chemistry, Northwestern University, Evanston, IL 60208, USA. ; Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA. t-ohalloran@northwestern.edu a-mondragon@northwestern.edu. ; Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA. Department of Chemistry, Northwestern University, Evanston, IL 60208, USA. The Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA. t-ohalloran@northwestern.edu a-mondragon@northwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26293965" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Allosteric Site ; Bacterial Proteins/chemistry/*metabolism ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; DNA-Binding Proteins/chemistry/*metabolism ; DNA-Directed RNA Polymerases/metabolism ; Nucleic Acid Conformation ; Promoter Regions, Genetic/*genetics ; Protein Multimerization ; Protein Structure, Secondary ; *Transcription, Genetic ; *Transcriptional Activation
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  • 72
    Publication Date: 2015-02-07
    Description: Mapping protein sequence space is a difficult problem that necessitates the analysis of 20(N) combinations for sequences of length N. We systematically mapped the sequence space of four key residues in the Escherichia coli protein kinase PhoQ that drive recognition of its substrate PhoP. We generated a library containing all 160,000 variants of PhoQ at these positions and used a two-step selection coupled to next-generation sequencing to identify 1659 functional variants. Our results reveal extensive degeneracy in the PhoQ-PhoP interface and epistasis, with the effect of individual substitutions often highly dependent on context. Together, epistasis and the genetic code create a pattern of connectivity of functional variants in sequence space that likely constrains PhoQ evolution. Consequently, the diversity of PhoQ orthologs is substantially lower than that of functional PhoQ variants.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Podgornaia, Anna I -- Laub, Michael T -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Feb 6;347(6222):673-7. doi: 10.1126/science.1257360.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Computational & Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. laub@mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25657251" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence/genetics ; *Epistasis, Genetic ; Escherichia coli Proteins/*genetics/metabolism ; *Evolution, Molecular ; Gene Library ; *Genetic Code ; Molecular Sequence Data ; Protein Interaction Domains and Motifs/genetics ; Protein Interaction Mapping ; Selection, Genetic ; Substrate Specificity/genetics
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  • 73
    Publication Date: 2015-08-15
    Description: Astrocytes are important regulatory elements in brain function. They respond to neurotransmitters and release gliotransmitters that modulate synaptic transmission. However, the cell- and synapse-specificity of the functional relationship between astrocytes and neurons in certain brain circuits remains unknown. In the dorsal striatum, which mainly comprises two intermingled subtypes (striatonigral and striatopallidal) of medium spiny neurons (MSNs) and synapses belonging to two neural circuits (the direct and indirect pathways of the basal ganglia), subpopulations of astrocytes selectively responded to specific MSN subtype activity. These subpopulations of astrocytes released glutamate that selectively activated N-methyl-d-aspartate receptors in homotypic, but not heterotypic, MSNs. Likewise, astrocyte subpopulations selectively regulated homotypic synapses through metabotropic glutamate receptor activation. Therefore, bidirectional astrocyte-neuron signaling selectively occurs between specific subpopulations of astrocytes, neurons, and synapses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martin, R -- Bajo-Graneras, R -- Moratalla, R -- Perea, G -- Araque, A -- New York, N.Y. -- Science. 2015 Aug 14;349(6249):730-4. doi: 10.1126/science.aaa7945.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Instituto Cajal, Consejo Superior de Investigaciones Cientificas, 28002 Madrid, Spain. ; Instituto Cajal, Consejo Superior de Investigaciones Cientificas, 28002 Madrid, Spain. Centro de Investigacion Biomedica en Red Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, 28029 Madrid, Spain. ; Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA. araque@umn.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26273054" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Astrocytes/*physiology ; Basal Ganglia/cytology/*physiology ; Cell Communication ; Glutamates/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Nerve Net/physiology ; Neurons/*physiology ; Receptors, Metabotropic Glutamate/agonists/metabolism ; Receptors, N-Methyl-D-Aspartate/agonists/metabolism ; Signal Transduction ; Synapses/*physiology ; *Synaptic Transmission
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  • 74
    Publication Date: 2015-09-05
    Description: Fusion of intracellular transport vesicles requires soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and Sec1/Munc18-family (SM) proteins. Membrane-bridging SNARE complexes are critical for fusion, but their spontaneous assembly is inefficient and may require SM proteins in vivo. We report x-ray structures of Vps33, the SM subunit of the yeast homotypic fusion and vacuole protein-sorting (HOPS) complex, bound to two individual SNAREs. The two SNAREs, one from each membrane, are held in the correct orientation and register for subsequent complex assembly. Vps33 and potentially other SM proteins could thus act as templates for generating partially zipped SNARE assembly intermediates. HOPS was essential to mediate SNARE complex assembly at physiological SNARE concentrations. Thus, Vps33 appears to catalyze SNARE complex assembly through specific SNARE motif recognition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4727825/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4727825/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baker, Richard W -- Jeffrey, Philip D -- Zick, Michael -- Phillips, Ben P -- Wickner, William T -- Hughson, Frederick M -- GM071574/GM/NIGMS NIH HHS/ -- GM23377/GM/NIGMS NIH HHS/ -- R01 GM071574/GM/NIGMS NIH HHS/ -- T32 GM007388/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Sep 4;349(6252):1111-4. doi: 10.1126/science.aac7906.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. ; Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. ; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. hughson@princeton.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26339030" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Membrane Proteins/chemistry/metabolism ; Munc18 Proteins/*metabolism ; Protein Binding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Qa-SNARE Proteins/*metabolism ; R-SNARE Proteins/*metabolism ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism/ultrastructure ; Synaptosomal-Associated Protein 25/chemistry/metabolism ; Vesicular Transport Proteins/chemistry/*metabolism/ultrastructure
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  • 75
    Publication Date: 2015-05-23
    Description: The 5' leader of the HIV-1 genome contains conserved elements that direct selective packaging of the unspliced, dimeric viral RNA into assembling particles. By using a (2)H-edited nuclear magnetic resonance (NMR) approach, we determined the structure of a 155-nucleotide region of the leader that is independently capable of directing packaging (core encapsidation signal; Psi(CES)). The RNA adopts an unexpected tandem three-way junction structure, in which residues of the major splice donor and translation initiation sites are sequestered by long-range base pairing and guanosines essential for both packaging and high-affinity binding to the cognate Gag protein are exposed in helical junctions. The structure reveals how translation is attenuated, Gag binding promoted, and unspliced dimeric genomes selected, by the RNA conformer that directs packaging.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492308/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492308/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Keane, Sarah C -- Heng, Xiao -- Lu, Kun -- Kharytonchyk, Siarhei -- Ramakrishnan, Venkateswaran -- Carter, Gregory -- Barton, Shawn -- Hosic, Azra -- Florwick, Alyssa -- Santos, Justin -- Bolden, Nicholas C -- McCowin, Sayo -- Case, David A -- Johnson, Bruce A -- Salemi, Marco -- Telesnitsky, Alice -- Summers, Michael F -- 2T34 GM008663/GM/NIGMS NIH HHS/ -- P50 GM 103297/GM/NIGMS NIH HHS/ -- P50 GM103297/GM/NIGMS NIH HHS/ -- R01 GM042561/GM/NIGMS NIH HHS/ -- R01 GM42561/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 May 22;348(6237):917-21. doi: 10.1126/science.aaa9266.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute (HHMI) and Department of Chemistry and Biochemistry, University of Maryland Baltimore County (UMBC), 1000 Hilltop Circle, Baltimore, MD 21250, USA. ; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620, USA. ; Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA. ; One Moon Scientific, Incorporated, 839 Grant Avenue, Westfield, NJ 07090, USA, and City University of New York (CUNY) Advanced Science Research Center, 85 St. Nicholas Terrace, New York, NY 10031, USA. ; Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, and Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, USA. ; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620, USA. summers@hhmi.umbc.edu ateles@umich.edu. ; Howard Hughes Medical Institute (HHMI) and Department of Chemistry and Biochemistry, University of Maryland Baltimore County (UMBC), 1000 Hilltop Circle, Baltimore, MD 21250, USA. summers@hhmi.umbc.edu ateles@umich.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25999508" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Genome, Viral ; Guanosine/chemistry ; HIV-1/*chemistry/genetics/*physiology ; Molecular Sequence Data ; Nuclear Magnetic Resonance, Biomolecular ; Nucleic Acid Conformation ; Peptide Chain Initiation, Translational ; RNA Splicing ; RNA, Viral/*chemistry/genetics ; *Virus Assembly ; gag Gene Products, Human Immunodeficiency Virus/chemistry
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  • 76
    Publication Date: 2015-06-27
    Description: Light-gated rhodopsin cation channels from chlorophyte algae have transformed neuroscience research through their use as membrane-depolarizing optogenetic tools for targeted photoactivation of neuron firing. Photosuppression of neuronal action potentials has been limited by the lack of equally efficient tools for membrane hyperpolarization. We describe anion channel rhodopsins (ACRs), a family of light-gated anion channels from cryptophyte algae that provide highly sensitive and efficient membrane hyperpolarization and neuronal silencing through light-gated chloride conduction. ACRs strictly conducted anions, completely excluding protons and larger cations, and hyperpolarized the membrane of cultured animal cells with much faster kinetics at less than one-thousandth of the light intensity required by the most efficient currently available optogenetic proteins. Natural ACRs provide optogenetic inhibition tools with unprecedented light sensitivity and temporal precision.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764398/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764398/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Govorunova, Elena G -- Sineshchekov, Oleg A -- Janz, Roger -- Liu, Xiaoqin -- Spudich, John L -- R01 GM027750/GM/NIGMS NIH HHS/ -- R01GM027750/GM/NIGMS NIH HHS/ -- R21MH098288/MH/NIMH NIH HHS/ -- S10RR022531/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2015 Aug 7;349(6248):647-50. doi: 10.1126/science.aaa7484. Epub 2015 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Membrane Biology, Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston, TX 77030, USA. ; Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, TX 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26113638" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Chloride Channels/classification/genetics/*physiology ; Cryptophyta/genetics/*metabolism ; HEK293 Cells ; Humans ; Ion Channel Gating ; Light ; Membrane Potentials/physiology/*radiation effects ; Molecular Sequence Data ; Neural Inhibition ; Neurons/physiology/*radiation effects ; Optogenetics/*methods ; Photic Stimulation ; Phylogeny ; Rhodopsins, Microbial/classification/genetics/*physiology ; Transfection
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  • 77
    Publication Date: 2015-03-07
    Description: Tail-anchored (TA) proteins are a physiologically important class of membrane proteins targeted to the endoplasmic reticulum by the conserved guided-entry of TA proteins (GET) pathway. During transit, their hydrophobic transmembrane domains (TMDs) are chaperoned by the cytosolic targeting factor Get3, but the molecular nature of the functional Get3-TA protein targeting complex remains unknown. We reconstituted the physiologic assembly pathway for a functional targeting complex and showed that it comprises a TA protein bound to a Get3 homodimer. Crystal structures of Get3 bound to different TA proteins showed an alpha-helical TMD occupying a hydrophobic groove that spans the Get3 homodimer. Our data elucidate the mechanism of TA protein recognition and shielding by Get3 and suggest general principles of hydrophobic domain chaperoning by cellular targeting factors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413028/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413028/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mateja, Agnieszka -- Paduch, Marcin -- Chang, Hsin-Yang -- Szydlowska, Anna -- Kossiakoff, Anthony A -- Hegde, Ramanujan S -- Keenan, Robert J -- MC_UP_A022_1007/Medical Research Council/United Kingdom -- P41 GM103403/GM/NIGMS NIH HHS/ -- R01 GM086487/GM/NIGMS NIH HHS/ -- U01 GM094588/GM/NIGMS NIH HHS/ -- U54 GM087519/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Mar 6;347(6226):1152-5. doi: 10.1126/science.1261671.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA. ; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. rhegde@mrc-lmb.cam.ac.uk bkeenan@uchicago.edu. ; Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA. rhegde@mrc-lmb.cam.ac.uk bkeenan@uchicago.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25745174" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/*chemistry/metabolism ; Crystallography, X-Ray ; Cytosol/enzymology ; Guanine Nucleotide Exchange Factors/*chemistry/metabolism ; Hydrophobic and Hydrophilic Interactions ; Membrane Proteins/*chemistry/metabolism ; Molecular Chaperones/chemistry/metabolism ; Multiprotein Complexes/chemistry/metabolism ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Protein Transport ; Saccharomyces cerevisiae Proteins/*chemistry/metabolism
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  • 78
    Publication Date: 2015-10-13
    Description: The shortage of organs for transplantation is a major barrier to the treatment of organ failure. Although porcine organs are considered promising, their use has been checked by concerns about the transmission of porcine endogenous retroviruses (PERVs) to humans. Here we describe the eradication of all PERVs in a porcine kidney epithelial cell line (PK15). We first determined the PK15 PERV copy number to be 62. Using CRISPR-Cas9, we disrupted all copies of the PERV pol gene and demonstrated a 〉1000-fold reduction in PERV transmission to human cells, using our engineered cells. Our study shows that CRISPR-Cas9 multiplexability can be as high as 62 and demonstrates the possibility that PERVs can be inactivated for clinical application of porcine-to-human xenotransplantation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Luhan -- Guell, Marc -- Niu, Dong -- George, Haydy -- Lesha, Emal -- Grishin, Dennis -- Aach, John -- Shrock, Ellen -- Xu, Weihong -- Poci, Jurgen -- Cortazio, Rebeca -- Wilkinson, Robert A -- Fishman, Jay A -- Church, George -- P50 HG005550/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2015 Nov 27;350(6264):1101-4. doi: 10.1126/science.aad1191. Epub 2015 Oct 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Harvard Medical School, Boston, MA, USA. Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, USA. eGenesis Biosciences, Boston, MA 02115, USA. gchurch@genetics.med.harvard.edu luhan.yang@egenesisbio.com. ; Department of Genetics, Harvard Medical School, Boston, MA, USA. Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, USA. eGenesis Biosciences, Boston, MA 02115, USA. ; Department of Genetics, Harvard Medical School, Boston, MA, USA. College of Animal Sciences, Zhejiang University, Hangzhou 310058, China. ; Department of Genetics, Harvard Medical School, Boston, MA, USA. ; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. ; Transplant Infectious Disease and Compromised Host Program, Massachusetts General Hospital, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26456528" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; CRISPR-Cas Systems ; Cell Line ; Endogenous Retroviruses/*genetics ; Epithelial Cells/virology ; Gene Dosage ; Gene Targeting/*methods ; Genes, pol ; HEK293 Cells ; Humans ; Kidney/virology ; Molecular Sequence Data ; Retroviridae Infections/*prevention & control/transmission/virology ; Swine/*virology ; Transplantation, Heterologous/*methods ; *Virus Inactivation
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  • 79
    Publication Date: 2015-08-15
    Description: Most spontaneous DNA double-strand breaks (DSBs) result from replication-fork breakage. Break-induced replication (BIR), a genome rearrangement-prone repair mechanism that requires the Pol32/POLD3 subunit of eukaryotic DNA Poldelta, was proposed to repair broken forks, but how genome destabilization is avoided was unknown. We show that broken fork repair initially uses error-prone Pol32-dependent synthesis, but that mutagenic synthesis is limited to within a few kilobases from the break by Mus81 endonuclease and a converging fork. Mus81 suppresses template switches between both homologous sequences and diverged human Alu repetitive elements, highlighting its importance for stability of highly repetitive genomes. We propose that lack of a timely converging fork or Mus81 may propel genome instability observed in cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mayle, Ryan -- Campbell, Ian M -- Beck, Christine R -- Yu, Yang -- Wilson, Marenda -- Shaw, Chad A -- Bjergbaek, Lotte -- Lupski, James R -- Ira, Grzegorz -- F31 NS083159/NS/NINDS NIH HHS/ -- GM080600/GM/NIGMS NIH HHS/ -- HG006542/HG/NHGRI NIH HHS/ -- NS058529/NS/NINDS NIH HHS/ -- NS083159/NS/NINDS NIH HHS/ -- R01 GM080600/GM/NIGMS NIH HHS/ -- R01 NS058529/NS/NINDS NIH HHS/ -- U54 HG006542/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2015 Aug 14;349(6249):742-7. doi: 10.1126/science.aaa8391.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. ; Department of Molecular Biology and Genetics, University of Aarhus, Aarhus 8000, Denmark. ; Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Department of Pediatrics, and Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Texas Children's Hospital, Houston, TX 77030, USA. ; Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. gira@bcm.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26273056" target="_blank"〉PubMed〈/a〉
    Keywords: Alu Elements ; Base Sequence ; *DNA Breaks, Double-Stranded ; DNA Repair/*genetics ; DNA Replication/*genetics ; DNA-Binding Proteins/genetics/*metabolism ; DNA-Directed DNA Polymerase/metabolism ; Endonucleases/genetics/*metabolism ; *Genomic Instability ; Humans ; Molecular Sequence Data ; Neoplasms/genetics ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism
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  • 80
    Publication Date: 2015-08-22
    Description: Transcription by RNA polymerase (RNAP) in bacteria requires specific promoter recognition by sigma factors. The major variant sigma factor (sigma(54)) initially forms a transcriptionally silent complex requiring specialized adenosine triphosphate-dependent activators for initiation. Our crystal structure of the 450-kilodalton RNAP-sigma(54) holoenzyme at 3.8 angstroms reveals molecular details of sigma(54) and its interactions with RNAP. The structure explains how sigma(54) targets different regions in RNAP to exert its inhibitory function. Although sigma(54) and the major sigma factor, sigma(70), have similar functional domains and contact similar regions of RNAP, unanticipated differences are observed in their domain arrangement and interactions with RNAP, explaining their distinct properties. Furthermore, we observe evolutionarily conserved regulatory hotspots in RNAPs that can be targeted by a diverse range of mechanisms to fine tune transcription.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681505/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681505/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Yun -- Darbari, Vidya C -- Zhang, Nan -- Lu, Duo -- Glyde, Robert -- Wang, Yi-Ping -- Winkelman, Jared T -- Gourse, Richard L -- Murakami, Katsuhiko S -- Buck, Martin -- Zhang, Xiaodong -- 098412/Wellcome Trust/United Kingdom -- BB/C504700/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- GM087350/GM/NIGMS NIH HHS/ -- R01 GM087350/GM/NIGMS NIH HHS/ -- R37 GM37048/GM/NIGMS NIH HHS/ -- Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Aug 21;349(6250):882-5. doi: 10.1126/science.aab1478.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Structural Biology, Imperial College London, South Kensington SW7 2AZ, UK. State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, China. ; Centre for Structural Biology, Imperial College London, South Kensington SW7 2AZ, UK. Department of Medicine, Imperial College London, South Kensington SW7 2AZ, UK. ; Department of Life Sciences, Imperial College London, South Kensington SW7 2AZ, UK. ; Centre for Structural Biology, Imperial College London, South Kensington SW7 2AZ, UK. ; State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, China. ; Department of Bacteriology, University of Wisconsin, Madison, WI 53706, USA. ; Department of Biochemistry and Molecular Biology, Center for RNA Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA. ; Centre for Structural Biology, Imperial College London, South Kensington SW7 2AZ, UK. Department of Medicine, Imperial College London, South Kensington SW7 2AZ, UK. xiaodong.zhang@imperial.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26293966" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Enzyme Stability ; *Evolution, Molecular ; *Gene Expression Regulation ; Holoenzymes/chemistry ; Protein Conformation ; Protein Structure, Tertiary ; RNA Polymerase Sigma 54/*chemistry/genetics ; *Transcription, Genetic
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  • 81
    Publication Date: 2015-06-06
    Description: The detailed molecular interactions between native HIV-1 capsid protein (CA) hexamers that shield the viral genome and proteins have been elusive. We report crystal structures describing interactions between CA monomers related by sixfold symmetry within hexamers (intrahexamer) and threefold and twofold symmetry between neighboring hexamers (interhexamer). The structures describe how CA builds hexagonal lattices, the foundation of mature capsids. Lattice structure depends on an adaptable hydration layer modulating interactions among CA molecules. Disruption of this layer alters interhexamer interfaces, highlighting an inherent structural variability. A CA-targeting antiviral affects capsid stability by binding across CA molecules and subtly altering interhexamer interfaces remote to the ligand-binding site. Inherent structural plasticity, hydration layer rearrangement, and effector binding affect capsid stability and have functional implications for the retroviral life cycle.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4584149/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4584149/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gres, Anna T -- Kirby, Karen A -- KewalRamani, Vineet N -- Tanner, John J -- Pornillos, Owen -- Sarafianos, Stefan G -- AI076119/AI/NIAID NIH HHS/ -- AI099284/AI/NIAID NIH HHS/ -- AI100890/AI/NIAID NIH HHS/ -- AI112417/AI/NIAID NIH HHS/ -- AI120860/AI/NIAID NIH HHS/ -- GM066087/GM/NIGMS NIH HHS/ -- GM103368/GM/NIGMS NIH HHS/ -- P50 GM103368/GM/NIGMS NIH HHS/ -- R01 AI076119/AI/NIAID NIH HHS/ -- R01 AI099284/AI/NIAID NIH HHS/ -- R01 AI100890/AI/NIAID NIH HHS/ -- R01 AI120860/AI/NIAID NIH HHS/ -- R01 GM066087/GM/NIGMS NIH HHS/ -- R21 AI112417/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2015 Jul 3;349(6243):99-103. doi: 10.1126/science.aaa5936. Epub 2015 Jun 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA. Department of Chemistry, University of Missouri, Columbia, MO 65211, USA. ; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA. Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65211, USA. ; Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. ; Department of Chemistry, University of Missouri, Columbia, MO 65211, USA. Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA. ; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. ; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA. Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65211, USA. Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA. sarafianoss@missouri.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26044298" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Capsid/*chemistry ; Crystallography, X-Ray ; HIV-1/*chemistry/genetics ; Molecular Sequence Data ; Protein Multimerization ; Protein Structure, Secondary ; gag Gene Products, Human Immunodeficiency Virus/*chemistry/genetics
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  • 82
    Publication Date: 2015-09-26
    Description: Dying cells initiate adaptive immunity by providing both antigens and inflammatory stimuli for dendritic cells, which in turn activate CD8(+) T cells through a process called antigen cross-priming. To define how different forms of programmed cell death influence immunity, we established models of necroptosis and apoptosis, in which dying cells are generated by receptor-interacting protein kinase-3 and caspase-8 dimerization, respectively. We found that the release of inflammatory mediators, such as damage-associated molecular patterns, by dying cells was not sufficient for CD8(+) T cell cross-priming. Instead, robust cross-priming required receptor-interacting protein kinase-1 (RIPK1) signaling and nuclear factor kappaB (NF-kappaB)-induced transcription within dying cells. Decoupling NF-kappaB signaling from necroptosis or inflammatory apoptosis reduced priming efficiency and tumor immunity. Our results reveal that coordinated inflammatory and cell death signaling pathways within dying cells orchestrate adaptive immunity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651449/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651449/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yatim, Nader -- Jusforgues-Saklani, Helene -- Orozco, Susana -- Schulz, Oliver -- Barreira da Silva, Rosa -- Reis e Sousa, Caetano -- Green, Douglas R -- Oberst, Andrew -- Albert, Matthew L -- 5R01AI108685-02/AI/NIAID NIH HHS/ -- AI44848/AI/NIAID NIH HHS/ -- R01 AI108685/AI/NIAID NIH HHS/ -- R01AI108685/AI/NIAID NIH HHS/ -- R21 CA185681/CA/NCI NIH HHS/ -- R21CA185681/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- New York, N.Y. -- Science. 2015 Oct 16;350(6258):328-34. doi: 10.1126/science.aad0395. Epub 2015 Sep 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, 25 Rue du Docteur Roux, 75015 Paris, France. Institut National de la Sante et de la Recherche Medicale, U818, 25 Rue du Docteur Roux, 75015 Paris, France. Frontieres du Vivant Doctoral School, Ecole Doctorale 474, Universite Paris Diderot-Paris 7, Sorbonne Paris Cite, 8-10 Rue Charles V, 75004 Paris, France. ; Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, 25 Rue du Docteur Roux, 75015 Paris, France. Institut National de la Sante et de la Recherche Medicale, U818, 25 Rue du Docteur Roux, 75015 Paris, France. ; Department of Immunology, University of Washington, Campus Box 358059, 750 Republican Street, Seattle, WA 98109, USA. ; Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. ; Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26405229" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis/*immunology ; CD8-Positive T-Lymphocytes/*immunology ; Caspase 8/metabolism ; Cell Survival ; Cross-Priming ; Dendritic Cells/immunology ; Mice ; Mice, Inbred C57BL ; NF-kappa B/*metabolism ; NIH 3T3 Cells ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics/*metabolism ; Signal Transduction
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  • 83
    Publication Date: 2015-05-09
    Description: Cryo-electron microscopy (cryo-EM) is rapidly emerging as a powerful tool for protein structure determination at high resolution. Here we report the structure of a complex between Escherichia coli beta-galactosidase and the cell-permeant inhibitor phenylethyl beta-D-thiogalactopyranoside (PETG), determined by cryo-EM at an average resolution of ~2.2 angstroms (A). Besides the PETG ligand, we identified densities in the map for ~800 water molecules and for magnesium and sodium ions. Although it is likely that continued advances in detector technology may further enhance resolution, our findings demonstrate that preparation of specimens of adequate quality and intrinsic protein flexibility, rather than imaging or image-processing technologies, now represent the major bottlenecks to routinely achieving resolutions close to 2 A using single-particle cryo-EM.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bartesaghi, Alberto -- Merk, Alan -- Banerjee, Soojay -- Matthies, Doreen -- Wu, Xiongwu -- Milne, Jacqueline L S -- Subramaniam, Sriram -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 5;348(6239):1147-51. doi: 10.1126/science.aab1576. Epub 2015 May 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. ; Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. ; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. ss1@nih.gov.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25953817" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Escherichia coli/*enzymology ; Escherichia coli Proteins/*chemistry ; Thiogalactosides/*chemistry ; Water/chemistry ; beta-Galactosidase/*chemistry
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  • 84
    Publication Date: 2015-04-25
    Description: In cells, biosynthetic machinery coordinates protein synthesis and folding to optimize efficiency and minimize off-pathway outcomes. However, it has been difficult to delineate experimentally the mechanisms responsible. Using fluorescence resonance energy transfer, we studied cotranslational folding of the first nucleotide-binding domain from the cystic fibrosis transmembrane conductance regulator. During synthesis, folding occurred discretely via sequential compaction of N-terminal, alpha-helical, and alpha/beta-core subdomains. Moreover, the timing of these events was critical; premature alpha-subdomain folding prevented subsequent core formation. This process was facilitated by modulating intrinsic folding propensity in three distinct ways: delaying alpha-subdomain compaction, facilitating beta-strand intercalation, and optimizing translation kinetics via codon usage. Thus, de novo folding is translationally tuned by an integrated cellular response that shapes the cotranslational folding landscape at critical stages of synthesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Soo Jung -- Yoon, Jae Seok -- Shishido, Hideki -- Yang, Zhongying -- Rooney, LeeAnn A -- Barral, Jose M -- Skach, William R -- P30CA069533/CA/NCI NIH HHS/ -- P30EYE010572/PHS HHS/ -- R01DK51818/DK/NIDDK NIH HHS/ -- R01GM53457/GM/NIGMS NIH HHS/ -- S10OD012246/OD/NIH HHS/ -- S10RR025571/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2015 Apr 24;348(6233):444-8. doi: 10.1126/science.aaa3974.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, Oregon Health and Science University (OHSU), Portland, OR 97239, USA. ; Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77550-0620, USA. Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77550-0620, USA. ; Department of Biochemistry and Molecular Biology, Oregon Health and Science University (OHSU), Portland, OR 97239, USA. Cystic Fibrosis Foundation Therapeutics, Bethesda, MD 20814, USA. skachw@ohsu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25908822" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Codon/chemistry/*metabolism ; Cystic Fibrosis Transmembrane Conductance ; Regulator/*biosynthesis/*chemistry/genetics ; Fluorescence Resonance Energy Transfer ; Humans ; Kinetics ; Molecular Sequence Data ; *Peptide Chain Elongation, Translational ; *Protein Folding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Ribosomes/chemistry/metabolism
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  • 85
    Publication Date: 2015-01-24
    Description: Chemokines and their receptors control cell migration during development, immune system responses, and in numerous diseases, including inflammation and cancer. The structural basis of receptor:chemokine recognition has been a long-standing unanswered question due to the challenges of structure determination for membrane protein complexes. Here, we report the crystal structure of the chemokine receptor CXCR4 in complex with the viral chemokine antagonist vMIP-II at 3.1 angstrom resolution. The structure revealed a 1:1 stoichiometry and a more extensive binding interface than anticipated from the paradigmatic two-site model. The structure helped rationalize a large body of mutagenesis data and together with modeling provided insights into CXCR4 interactions with its endogenous ligand CXCL12, its ability to recognize diverse ligands, and the specificity of CC and CXC receptors for their respective chemokines.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362693/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362693/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qin, Ling -- Kufareva, Irina -- Holden, Lauren G -- Wang, Chong -- Zheng, Yi -- Zhao, Chunxia -- Fenalti, Gustavo -- Wu, Huixian -- Han, Gye Won -- Cherezov, Vadim -- Abagyan, Ruben -- Stevens, Raymond C -- Handel, Tracy M -- ACB-12002/PHS HHS/ -- AGM-12006/PHS HHS/ -- R01 GM071872/GM/NIGMS NIH HHS/ -- R01 GM081763/GM/NIGMS NIH HHS/ -- R21 AI101687/AI/NIAID NIH HHS/ -- U01 GM094612/GM/NIGMS NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Mar 6;347(6226):1117-22. doi: 10.1126/science.1261064. Epub 2015 Jan 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92093, USA. ; University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92093, USA. thandel@ucsd.edu stevens@usc.edu ikufareva@ucsd.edu. ; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. ; Department of Chemistry, Bridge Institute. Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA. ; Department of Chemistry, Bridge Institute. ; Department of Chemistry, Bridge Institute. Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA. thandel@ucsd.edu stevens@usc.edu ikufareva@ucsd.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25612609" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Chemokine CXCL12/chemistry ; Chemokines/*chemistry ; Crystallography, X-Ray ; Drug Design ; Humans ; Models, Chemical ; Molecular Sequence Data ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Multimerization ; Receptors, CXCR4/agonists/antagonists & inhibitors/*chemistry ; Structural Homology, Protein
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  • 86
    Publication Date: 2015-05-30
    Description: Photosynthesis converts solar energy to chemical energy by means of two large pigment-protein complexes: photosystem I (PSI) and photosystem II (PSII). In higher plants, the PSI core is surrounded by a large light-harvesting complex I (LHCI) that captures sunlight and transfers the excitation energy to the core with extremely high efficiency. We report the structure of PSI-LHCI, a 600-kilodalton membrane protein supercomplex, from Pisum sativum (pea) at a resolution of 2.8 angstroms. The structure reveals the detailed arrangement of pigments and other cofactors-especially within LHCI-as well as numerous specific interactions between the PSI core and LHCI. These results provide a firm structural basis for our understanding on the energy transfer and photoprotection mechanisms within the PSI-LHCI supercomplex.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qin, Xiaochun -- Suga, Michihiro -- Kuang, Tingyun -- Shen, Jian-Ren -- New York, N.Y. -- Science. 2015 May 29;348(6238):989-95. doi: 10.1126/science.aab0214.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Photosynthesis Research Center, Key Laboratory of Photobiology, Institute of Botany, Chinese Academy of Sciences, Beijing 100093, China. Photosynthesis Research Center, Graduate School of Natural Science and Technology, Okayama University, Tsushima Naka 3-1-1, Okayama 700-8530, Japan. ; Photosynthesis Research Center, Graduate School of Natural Science and Technology, Okayama University, Tsushima Naka 3-1-1, Okayama 700-8530, Japan. ; Photosynthesis Research Center, Key Laboratory of Photobiology, Institute of Botany, Chinese Academy of Sciences, Beijing 100093, China. kuangty@ibcas.ac.cn shen@cc.okayama-u.ac.jp. ; Photosynthesis Research Center, Key Laboratory of Photobiology, Institute of Botany, Chinese Academy of Sciences, Beijing 100093, China. Photosynthesis Research Center, Graduate School of Natural Science and Technology, Okayama University, Tsushima Naka 3-1-1, Okayama 700-8530, Japan. kuangty@ibcas.ac.cn shen@cc.okayama-u.ac.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26023133" target="_blank"〉PubMed〈/a〉
    Keywords: Carotenoids/chemistry ; Crystallography, X-Ray ; Energy Transfer ; Light-Harvesting Protein Complexes/*chemistry/ultrastructure ; Peas/*enzymology ; *Photosynthesis ; Photosystem I Protein Complex/*chemistry/ultrastructure ; Protein Structure, Secondary
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  • 87
    Publication Date: 2015-08-01
    Description: The inefficient clearance of dying cells can lead to abnormal immune responses, such as unresolved inflammation and autoimmune conditions. We show that tumor suppressor p53 controls signaling-mediated phagocytosis of apoptotic cells through its target, Death Domain1alpha (DD1alpha), which suggests that p53 promotes both the proapoptotic pathway and postapoptotic events. DD1alpha appears to function as an engulfment ligand or receptor that engages in homophilic intermolecular interaction at intercellular junctions of apoptotic cells and macrophages, unlike other typical scavenger receptors that recognize phosphatidylserine on the surface of dead cells. DD1alpha-deficient mice showed in vivo defects in clearing dying cells, which led to multiple organ damage indicative of immune dysfunction. p53-induced expression of DD1alpha thus prevents persistence of cell corpses and ensures efficient generation of precise immune responses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yoon, Kyoung Wan -- Byun, Sanguine -- Kwon, Eunjeong -- Hwang, So-Young -- Chu, Kiki -- Hiraki, Masatsugu -- Jo, Seung-Hee -- Weins, Astrid -- Hakroush, Samy -- Cebulla, Angelika -- Sykes, David B -- Greka, Anna -- Mundel, Peter -- Fisher, David E -- Mandinova, Anna -- Lee, Sam W -- CA142805/CA/NCI NIH HHS/ -- CA149477/CA/NCI NIH HHS/ -- CA80058/CA/NCI NIH HHS/ -- DK062472/DK/NIDDK NIH HHS/ -- DK091218/DK/NIDDK NIH HHS/ -- DK093378/DK/NIDDK NIH HHS/ -- DK57683/DK/NIDDK NIH HHS/ -- S10RR027673/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2015 Jul 31;349(6247):1261669. doi: 10.1126/science.1261669.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA. ; Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA. ; Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. ; Center for Regenerative Medicine and Technology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. ; Department of Medicine, Glom-NExT Center for Glomerular Kidney Disease and Novel Experimental Therapeutics, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA. ; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA. ; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA. swlee@mgh.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26228159" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Apoptosis/genetics/*immunology ; Autoimmune Diseases/genetics/immunology ; Cell Line, Tumor ; Female ; Humans ; Inflammation/genetics/immunology ; Macrophages/immunology ; Male ; Membrane Proteins/genetics/*metabolism ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Phagocytosis/*immunology ; Phosphatidylserines/*metabolism ; Signal Transduction ; Tumor Suppressor Protein p53/*metabolism
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  • 88
    Publication Date: 2015-04-25
    Description: The Protoaurignacian culture is pivotal to the debate about the timing of the arrival of modern humans in western Europe and the demise of Neandertals. However, which group is responsible for this culture remains uncertain. We investigated dental remains associated with the Protoaurignacian. The lower deciduous incisor from Riparo Bombrini is modern human, based on its morphology. The upper deciduous incisor from Grotta di Fumane contains ancient mitochondrial DNA of a modern human type. These teeth are the oldest human remains in an Aurignacian-related archaeological context, confirming that by 41,000 calendar years before the present, modern humans bearing Protoaurignacian culture spread into southern Europe. Because the last Neandertals date to 41,030 to 39,260 calendar years before the present, we suggest that the Protoaurignacian triggered the demise of Neandertals in this area.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Benazzi, S -- Slon, V -- Talamo, S -- Negrino, F -- Peresani, M -- Bailey, S E -- Sawyer, S -- Panetta, D -- Vicino, G -- Starnini, E -- Mannino, M A -- Salvadori, P A -- Meyer, M -- Paabo, S -- Hublin, J-J -- New York, N.Y. -- Science. 2015 May 15;348(6236):793-6. doi: 10.1126/science.aaa2773. Epub 2015 Apr 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cultural Heritage, University of Bologna, Via degli Ariani 1, 48121 Ravenna, Italy. Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany. stefano.benazzi@unibo.it. ; Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany. ; Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany. ; Dipartimento di Antichita, Filosofia, Storia e Geografia, Universita di Genova, Via Balbi 2, 16126 Genova, Italy. ; Sezione di Scienze Preistoriche e Antropologiche, Dipartimento di Studi Umanistici, Corso Ercole I d'Este 32, Universita di Ferrara, 44100 Ferrara, Italy. ; Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany. Center for the Study of Human Origins, Department of Anthropology, New York University, 25 Waverly Place, New York, NY 10003, USA. ; CNR Institute of Clinical Physiology, National Research Council, Via G. Moruzzi 1, 56124 Pisa, Italy. ; Museo Archeologico del Finale, Chiostri di Santa Caterina, 17024 Finale Ligure Borgo, Italy. ; Scuola di Scienze Umanistiche, Dipartimento di Studi Storici, Universita di Torino, via S. Ottavio 20, 10124 Torino, Italy. Museo Preistorico Nazionale dei Balzi Rossi, Via Balzi Rossi 9, 18039 Ventimiglia, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25908660" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Archaeology ; Base Sequence ; DNA, Mitochondrial/analysis/genetics ; Dental Enamel/chemistry ; *Extinction, Biological ; Genome, Mitochondrial/genetics ; Humans ; Incisor/anatomy & histology/chemistry ; Molecular Sequence Data ; Neanderthals/anatomy & histology/*classification/*genetics ; *Phylogeny ; Tooth, Deciduous/anatomy & histology/chemistry
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  • 89
    Publication Date: 2015-11-21
    Description: Drosophila intestinal stem cells (ISCs) generate enterocytes (ECs) and enteroendocrine (ee) cells. Previous work suggests that different levels of the Notch ligand Delta (Dl) in ISCs unidirectionally activate Notch in daughters to control multipotency. However, the mechanisms driving different outcomes remain unknown. We found that during ee cell formation, the ee cell marker Prospero localizes to the basal side of dividing ISCs. After asymmetric division, the ee daughter cell acts as a source of Dl that induces low Notch activity in the ISC to maintain identity. Alternatively, ISCs expressing Dl induce high Notch activity in daughter cells to promote EC formation. Our data reveal a conserved role for Notch in Drosophila and mammalian ISC maintenance and suggest that bidirectional Notch signaling may regulate multipotency in other systems.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guo, Zheng -- Ohlstein, Benjamin -- New York, N.Y. -- Science. 2015 Nov 20;350(6263). pii: aab0988. doi: 10.1126/science.aab0988.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA. ; Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA. bo2160@columbia.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26586765" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Differentiation ; Cell Division ; Cell Polarity ; Drosophila Proteins/*metabolism ; Drosophila melanogaster/cytology/*growth & development/metabolism ; Enterocytes/*cytology ; Enteroendocrine Cells/*cytology ; Multipotent Stem Cells/*cytology/metabolism ; Nuclear Proteins/*metabolism ; Phosphoproteins/*metabolism ; Receptors, Notch/*metabolism ; Signal Transduction ; Transcription Factors/*metabolism
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  • 90
    Publication Date: 2015-09-01
    Description: The nuclear pore complex (NPC) constitutes the sole gateway for bidirectional nucleocytoplasmic transport. We present the reconstitution and interdisciplinary analyses of the ~425-kilodalton inner ring complex (IRC), which forms the central transport channel and diffusion barrier of the NPC, revealing its interaction network and equimolar stoichiometry. The Nsp1*Nup49*Nup57 channel nucleoporin heterotrimer (CNT) attaches to the IRC solely through the adaptor nucleoporin Nic96. The CNT*Nic96 structure reveals that Nic96 functions as an assembly sensor that recognizes the three-dimensional architecture of the CNT, thereby mediating the incorporation of a defined CNT state into the NPC. We propose that the IRC adopts a relatively rigid scaffold that recruits the CNT to primarily form the diffusion barrier of the NPC, rather than enabling channel dilation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stuwe, Tobias -- Bley, Christopher J -- Thierbach, Karsten -- Petrovic, Stefan -- Schilbach, Sandra -- Mayo, Daniel J -- Perriches, Thibaud -- Rundlet, Emily J -- Jeon, Young E -- Collins, Leslie N -- Huber, Ferdinand M -- Lin, Daniel H -- Paduch, Marcin -- Koide, Akiko -- Lu, Vincent -- Fischer, Jessica -- Hurt, Ed -- Koide, Shohei -- Kossiakoff, Anthony A -- Hoelz, Andre -- ACB-12002/PHS HHS/ -- AGM-12006/PHS HHS/ -- P30-CA014599/CA/NCI NIH HHS/ -- R01-GM090324/GM/NIGMS NIH HHS/ -- R01-GM111461/GM/NIGMS NIH HHS/ -- U01-GM094588/GM/NIGMS NIH HHS/ -- U54-GM087519/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Oct 2;350(6256):56-64. doi: 10.1126/science.aac9176. Epub 2015 Aug 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉California Institute of Technology, Division of Chemistry and Chemical Engineering, 1200 East California Boulevard, Pasadena, CA 91125, USA. ; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA. ; Biochemistry Center of Heidelberg University, 69120 Heidelberg, Germany. ; California Institute of Technology, Division of Chemistry and Chemical Engineering, 1200 East California Boulevard, Pasadena, CA 91125, USA. hoelz@caltech.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26316600" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Chaetomium/metabolism/*ultrastructure ; Fungal Proteins/chemistry/*ultrastructure ; Molecular Sequence Data ; Nuclear Pore/metabolism/*ultrastructure ; Nuclear Pore Complex Proteins/chemistry/*ultrastructure ; Nuclear Proteins/chemistry/*ultrastructure ; Protein Binding ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary
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  • 91
    Publication Date: 2015-09-19
    Description: A wide variety of RNAs encode small open-reading-frame (smORF/sORF) peptides, but their functions are largely unknown. Here, we show that Drosophila polished-rice (pri) sORF peptides trigger proteasome-mediated protein processing, converting the Shavenbaby (Svb) transcription repressor into a shorter activator. A genome-wide RNA interference screen identifies an E2-E3 ubiquitin-conjugating complex, UbcD6-Ubr3, which targets Svb to the proteasome in a pri-dependent manner. Upon interaction with Ubr3, Pri peptides promote the binding of Ubr3 to Svb. Ubr3 can then ubiquitinate the Svb N terminus, which is degraded by the proteasome. The C-terminal domains protect Svb from complete degradation and ensure appropriate processing. Our data show that Pri peptides control selectivity of Ubr3 binding, which suggests that the family of sORF peptides may contain an extended repertoire of protein regulators.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zanet, J -- Benrabah, E -- Li, T -- Pelissier-Monier, A -- Chanut-Delalande, H -- Ronsin, B -- Bellen, H J -- Payre, F -- Plaza, S -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Sep 18;349(6254):1356-8. doi: 10.1126/science.aac5677.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre de Biologie du Developpement, Universite de Toulouse III-Paul Sabatier, Batiment 4R3, 118 route de Narbonne, F-31062 Toulouse, France. CNRS, UMR5547, Centre de Biologie du Developpement, F-31062 Toulouse, France. ; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. ; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA. ; Centre de Biologie du Developpement, Universite de Toulouse III-Paul Sabatier, Batiment 4R3, 118 route de Narbonne, F-31062 Toulouse, France. CNRS, UMR5547, Centre de Biologie du Developpement, F-31062 Toulouse, France. francois.payre@univ-tlse3.fr serge.plaza@univ-tlse3.f.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26383956" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Drosophila Proteins/chemistry/genetics/*metabolism ; Drosophila melanogaster/enzymology/genetics/*metabolism ; Gene Expression Regulation ; Molecular Sequence Data ; Open Reading Frames ; Peptides/genetics/*metabolism ; Proteasome Endopeptidase Complex/*metabolism ; Protein Structure, Tertiary ; *Proteolysis ; RNA Interference ; Transcription Factors/chemistry/genetics/*metabolism ; Ubiquitin-Conjugating Enzymes/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
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  • 92
    Publication Date: 2015-01-31
    Description: Translocator proteins (TSPOs) bind steroids and porphyrins, and they are implicated in many human diseases, for which they serve as biomarkers and therapeutic targets. TSPOs have tryptophan-rich sequences that are highly conserved from bacteria to mammals. Here we report crystal structures for Bacillus cereus TSPO (BcTSPO) down to 1.7 A resolution, including a complex with the benzodiazepine-like inhibitor PK11195. We also describe BcTSPO-mediated protoporphyrin IX (PpIX) reactions, including catalytic degradation to a previously undescribed heme derivative. We used structure-inspired mutations to investigate reaction mechanisms, and we showed that TSPOs from Xenopus and man have similar PpIX-directed activities. Although TSPOs have been regarded as transporters, the catalytic activity in PpIX degradation suggests physiological importance for TSPOs in protection against oxidative stress.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4341906/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4341906/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guo, Youzhong -- Kalathur, Ravi C -- Liu, Qun -- Kloss, Brian -- Bruni, Renato -- Ginter, Christopher -- Kloppmann, Edda -- Rost, Burkhard -- Hendrickson, Wayne A -- GM095315/GM/NIGMS NIH HHS/ -- GM107462/GM/NIGMS NIH HHS/ -- R01 GM107462/GM/NIGMS NIH HHS/ -- U54 GM075026/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 30;347(6221):551-5. doi: 10.1126/science.aaa1534.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. ; The New York Consortium on Membrane Protein Structure (NYCOMPS), New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA. ; The New York Consortium on Membrane Protein Structure (NYCOMPS), New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA. New York Structural Biology Center, Synchrotron Beamlines, Brookhaven National Laboratory, Upton, NY 11973, USA. ; The New York Consortium on Membrane Protein Structure (NYCOMPS), New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA. Department of Informatics, Bioinformatics and Computational Biology, Technische Universitat Munchen, Garching 85748, Germany. ; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. The New York Consortium on Membrane Protein Structure (NYCOMPS), New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA. New York Structural Biology Center, Synchrotron Beamlines, Brookhaven National Laboratory, Upton, NY 11973, USA. Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA. wayne@xtl.cumc.columbia.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25635100" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Bacillus cereus/*chemistry ; Bacterial Proteins/*chemistry/*metabolism ; Binding Sites ; Crystallography, X-Ray ; Isoquinolines/metabolism ; Ligands ; Membrane Transport Proteins/*chemistry/*metabolism ; Molecular Sequence Data ; Mutant Proteins/chemistry/metabolism ; Protein Conformation ; Protein Multimerization ; Protein Structure, Secondary ; Protein Subunits/chemistry ; Protoporphyrins/metabolism ; Reactive Oxygen Species/metabolism ; Tryptophan/analysis
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  • 93
    Publication Date: 2015-03-07
    Description: The nuclear pore complex (NPC) constitutes the sole gateway for bidirectional nucleocytoplasmic transport. Despite half a century of structural characterization, the architecture of the NPC remains unknown. Here we present the crystal structure of a reconstituted ~400-kilodalton coat nucleoporin complex (CNC) from Saccharomyces cerevisiae at a 7.4 angstrom resolution. The crystal structure revealed a curved Y-shaped architecture and the molecular details of the coat nucleoporin interactions forming the central "triskelion" of the Y. A structural comparison of the yeast CNC with an electron microscopy reconstruction of its human counterpart suggested the evolutionary conservation of the elucidated architecture. Moreover, 32 copies of the CNC crystal structure docked readily into a cryoelectron tomographic reconstruction of the fully assembled human NPC, thereby accounting for ~16 megadalton of its mass.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stuwe, Tobias -- Correia, Ana R -- Lin, Daniel H -- Paduch, Marcin -- Lu, Vincent T -- Kossiakoff, Anthony A -- Hoelz, Andre -- 5 T32 GM07616/GM/NIGMS NIH HHS/ -- ACB-12002/PHS HHS/ -- AGM-12006/PHS HHS/ -- U01 GM094588/GM/NIGMS NIH HHS/ -- U54 GM087519/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Mar 6;347(6226):1148-52. doi: 10.1126/science.aaa4136. Epub 2015 Feb 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA. These authors contributed equally to this work. ; Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA. ; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA. ; Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA. hoelz@caltech.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25745173" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Humans ; Nuclear Pore/*ultrastructure ; Nuclear Pore Complex Proteins/*chemistry ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/*ultrastructure ; Saccharomyces cerevisiae Proteins/*chemistry
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  • 94
    Publication Date: 2015-05-09
    Description: In the fruit fly Drosophila, head formation is driven by a single gene, bicoid, which generates head-to-tail polarity of the main embryonic axis. Bicoid deficiency results in embryos with tail-to-tail polarity and no head. However, most insects lack bicoid, and the molecular mechanism for establishing head-to-tail polarity is poorly understood. We have identified a gene that establishes head-to-tail polarity of the mosquito-like midge, Chironomus riparius. This gene, named panish, encodes a cysteine-clamp DNA binding domain and operates through a different mechanism than bicoid. This finding, combined with the observation that the phylogenetic distributions of panish and bicoid are limited to specific families of flies, reveals frequent evolutionary changes of body axis determinants and a remarkable opportunity to study gene regulatory network evolution.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449817/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449817/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Klomp, Jeff -- Athy, Derek -- Kwan, Chun Wai -- Bloch, Natasha I -- Sandmann, Thomas -- Lemke, Steffen -- Schmidt-Ott, Urs -- 1R03HD67700-01A1/HD/NICHD NIH HHS/ -- R03 HD067700/HD/NICHD NIH HHS/ -- New York, N.Y. -- Science. 2015 May 29;348(6238):1040-2. doi: 10.1126/science.aaa7105. Epub 2015 May 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Organismal Biology and Anatomy, University of Chicago, Chicago, IL 60637, USA. ; Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Organismal Biology and Anatomy, University of Chicago, Chicago, IL 60637, USA. uschmid@uchicago.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25953821" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Body Patterning/*genetics ; Chironomidae/*embryology/genetics ; DNA-Binding Proteins/classification/genetics/*physiology ; Embryo, Nonmammalian/*embryology ; Evolution, Molecular ; Gene Expression Regulation, Developmental ; Gene Regulatory Networks ; Homeodomain Proteins/classification/genetics/*physiology ; Molecular Sequence Data ; Phylogeny ; Protein Structure, Tertiary/genetics ; Trans-Activators/classification/genetics/*physiology
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  • 95
    Publication Date: 2015-04-18
    Description: Measles is a highly contagious human disease. We used cryo-electron microscopy and single particle-based helical image analysis to determine the structure of the helical nucleocapsid formed by the folded domain of the measles virus nucleoprotein encapsidating an RNA at a resolution of 4.3 angstroms. The resulting pseudoatomic model of the measles virus nucleocapsid offers important insights into the mechanism of the helical polymerization of nucleocapsids of negative-strand RNA viruses, in particular via the exchange subdomains of the nucleoprotein. The structure reveals the mode of the nucleoprotein-RNA interaction and explains why each nucleoprotein of measles virus binds six nucleotides, whereas the respiratory syncytial virus nucleoprotein binds seven. It provides a rational basis for further analysis of measles virus replication and transcription, and reveals potential targets for drug design.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gutsche, Irina -- Desfosses, Ambroise -- Effantin, Gregory -- Ling, Wai Li -- Haupt, Melina -- Ruigrok, Rob W H -- Sachse, Carsten -- Schoehn, Guy -- New York, N.Y. -- Science. 2015 May 8;348(6235):704-7. doi: 10.1126/science.aaa5137. Epub 2015 Apr 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CNRS, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. Universite Grenoble Alpes, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. gutsche@embl.fr. ; Structural and Computational Biology Unit, European Molecular Biology Laboratory, 69917 Heidelberg, Germany. ; CNRS, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. Universite Grenoble Alpes, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. ; Universite Grenoble Alpes, IBS, 38044 Grenoble, France. CNRS, IBS, 38044 Grenoble, France. CEA, IBS, 38044 Grenoble, France. ; Institut Laue-Langevin, 38000 Grenoble, France. ; CNRS, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. Universite Grenoble Alpes, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. Universite Grenoble Alpes, IBS, 38044 Grenoble, France. CNRS, IBS, 38044 Grenoble, France. CEA, IBS, 38044 Grenoble, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25883315" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cryoelectron Microscopy ; Humans ; Measles/*virology ; Measles virus/chemistry/*ultrastructure ; Molecular Sequence Data ; Nucleic Acid Conformation ; Nucleocapsid/chemistry/*ultrastructure ; Nucleoproteins/chemistry/ultrastructure ; Protein Structure, Secondary ; RNA, Viral/chemistry/ultrastructure ; Viral Proteins/chemistry/ultrastructure
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  • 96
    Publication Date: 2015-06-06
    Description: The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kling, Angela -- Lukat, Peer -- Almeida, Deepak V -- Bauer, Armin -- Fontaine, Evelyne -- Sordello, Sylvie -- Zaburannyi, Nestor -- Herrmann, Jennifer -- Wenzel, Silke C -- Konig, Claudia -- Ammerman, Nicole C -- Barrio, Maria Belen -- Borchers, Kai -- Bordon-Pallier, Florence -- Bronstrup, Mark -- Courtemanche, Gilles -- Gerlitz, Martin -- Geslin, Michel -- Hammann, Peter -- Heinz, Dirk W -- Hoffmann, Holger -- Klieber, Sylvie -- Kohlmann, Markus -- Kurz, Michael -- Lair, Christine -- Matter, Hans -- Nuermberger, Eric -- Tyagi, Sandeep -- Fraisse, Laurent -- Grosset, Jacques H -- Lagrange, Sophie -- Muller, Rolf -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Jun 5;348(6239):1106-12. doi: 10.1126/science.aaa4690.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research and Pharmaceutical Biotechnology, Saarland University, 66123 Saarbrucken, Germany. German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany. ; Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research and Pharmaceutical Biotechnology, Saarland University, 66123 Saarbrucken, Germany. German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany. Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany. ; Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Durban 4001, South Africa. ; Sanofi-Aventis R&D, LGCR/Chemistry, Industriepark Hochst, 65926 Frankfurt am Main, Germany. ; Sanofi-Aventis R&D, Infectious Diseases Therapeutic Strategic Unit, 31036 Toulouse, France. ; Sanofi-Aventis R&D, Strategy, Science Policy & External Innovation (S&I), 75008 Paris, France. ; Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany. Sanofi-Aventis R&D, LGCR/Chemistry, Industriepark Hochst, 65926 Frankfurt am Main, Germany. ; Sanofi-Aventis R&D, Infectious Diseases Therapeutic Strategic Unit, 65926 Frankfurt, Germany. ; German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany. Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany. ; Sanofi-Aventis R&D, Disposition Safety and Animal Research, 34184 Montpellier, France. ; Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. ; Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research and Pharmaceutical Biotechnology, Saarland University, 66123 Saarbrucken, Germany. German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany. rolf.mueller@helmholtz-hzi.de.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26045430" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antitubercular Agents/chemistry/*pharmacology/therapeutic use ; Bacterial Proteins/*antagonists & inhibitors ; Cell Line, Tumor ; Crystallography, X-Ray ; DNA-Directed DNA Polymerase ; Disease Models, Animal ; Drug Design ; Humans ; Mice ; Microbial Sensitivity Tests ; Molecular Sequence Data ; *Molecular Targeted Therapy ; Mycobacterium smegmatis/drug effects/enzymology ; Mycobacterium tuberculosis/*drug effects/enzymology ; Peptides, Cyclic/chemistry/*pharmacology/therapeutic use ; Protein Structure, Secondary ; Streptomyces/chemistry/drug effects/metabolism ; Tuberculosis, Multidrug-Resistant/*drug therapy/microbiology
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  • 97
    Publication Date: 2015-10-10
    Description: Leucine is a proteogenic amino acid that also regulates many aspects of mammalian physiology, in large part by activating the mTOR complex 1 (mTORC1) protein kinase, a master growth controller. Amino acids signal to mTORC1 through the Rag guanosine triphosphatases (GTPases). Several factors regulate the Rags, including GATOR1, aGTPase-activating protein; GATOR2, a positive regulator of unknown function; and Sestrin2, a GATOR2-interacting protein that inhibits mTORC1 signaling. We find that leucine, but not arginine, disrupts the Sestrin2-GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20 micromolar, which is the leucine concentration that half-maximally activates mTORC1. The leucine-binding capacity of Sestrin2 is required for leucine to activate mTORC1 in cells. These results indicate that Sestrin2 is a leucine sensor for the mTORC1 pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698017/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698017/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wolfson, Rachel L -- Chantranupong, Lynne -- Saxton, Robert A -- Shen, Kuang -- Scaria, Sonia M -- Cantor, Jason R -- Sabatini, David M -- AI47389/AI/NIAID NIH HHS/ -- F30 CA189333/CA/NCI NIH HHS/ -- F31 CA180271/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R37 AI047389/AI/NIAID NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Jan 1;351(6268):43-8. doi: 10.1126/science.aab2674. Epub 2015 Oct 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. ; Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ; Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. sabatini@wi.mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26449471" target="_blank"〉PubMed〈/a〉
    Keywords: GTPase-Activating Proteins/*metabolism ; HEK293 Cells ; Humans ; Leucine/*metabolism ; Metabolic Networks and Pathways ; Multiprotein Complexes/*metabolism ; Nuclear Proteins/chemistry/genetics/*metabolism ; Protein Binding ; Proteins/chemistry/*metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/*metabolism
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  • 98
    Publication Date: 2015-12-19
    Description: Outbreaks of Middle East respiratory syndrome (MERS) raise questions about the prevalence and evolution of the MERS coronavirus (CoV) in its animal reservoir. Our surveillance in Saudi Arabia in 2014 and 2015 showed that viruses of the MERS-CoV species and a human CoV 229E-related lineage co-circulated at high prevalence, with frequent co-infections in the upper respiratory tract of dromedary camels. viruses of the betacoronavirus 1 species, we found that dromedary camels share three CoV species with humans. Several MERS-CoV lineages were present in camels, including a recombinant lineage that has been dominant since December 2014 and that subsequently led to the human outbreaks in 2015. Camels therefore serve as an important reservoir for the maintenance and diversification of the MERS-CoVs and are the source of human infections with this virus.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sabir, Jamal S M -- Lam, Tommy T-Y -- Ahmed, Mohamed M M -- Li, Lifeng -- Shen, Yongyi -- Abo-Aba, Salah E M -- Qureshi, Muhammd I -- Abu-Zeid, Mohamed -- Zhang, Yu -- Khiyami, Mohammad A -- Alharbi, Njud S -- Hajrah, Nahid H -- Sabir, Meshaal J -- Mutwakil, Mohammed H Z -- Kabli, Saleh A -- Alsulaimany, Faten A S -- Obaid, Abdullah Y -- Zhou, Boping -- Smith, David K -- Holmes, Edward C -- Zhu, Huachen -- Guan, Yi -- New York, N.Y. -- Science. 2016 Jan 1;351(6268):81-4. doi: 10.1126/science.aac8608. Epub 2015 Dec 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biotechnology Research Group, Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia. ; State Key Laboratory of Emerging Infectious Diseases (The University of Hong Kong-Shenzhen Branch), Shenzhen Third People's Hospital, Shenzhen, China. Shantou University-The University of Hong Kong Joint Institute of Virology, Shantou University, Shantou, China. Centre of Influenza Research and State Key Laboratory of Emerging Infectious Diseases, School of Public Health, The University of Hong Kong, Hong Kong Special Administrative Region, China. ; Biotechnology Research Group, Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia. Department of Nucleic Acids Research, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, Borg El-Arab, Post Office Box 21934, Alexandria, Egypt. ; Shantou University-The University of Hong Kong Joint Institute of Virology, Shantou University, Shantou, China. Centre of Influenza Research and State Key Laboratory of Emerging Infectious Diseases, School of Public Health, The University of Hong Kong, Hong Kong Special Administrative Region, China. ; Biotechnology Research Group, Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia. Microbial Genetics Department, Genetic Engineering and Biotechnology Division, National Research Center, Dokki, Giza, Egypt. ; King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia. ; Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia. ; State Key Laboratory of Emerging Infectious Diseases (The University of Hong Kong-Shenzhen Branch), Shenzhen Third People's Hospital, Shenzhen, China. ; Centre of Influenza Research and State Key Laboratory of Emerging Infectious Diseases, School of Public Health, The University of Hong Kong, Hong Kong Special Administrative Region, China. ; Marie Bashir Institute for Infectious Diseases and Biosecurity, Charles Perkins Centre, School of Biological Sciences and Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia. ; State Key Laboratory of Emerging Infectious Diseases (The University of Hong Kong-Shenzhen Branch), Shenzhen Third People's Hospital, Shenzhen, China. Shantou University-The University of Hong Kong Joint Institute of Virology, Shantou University, Shantou, China. Centre of Influenza Research and State Key Laboratory of Emerging Infectious Diseases, School of Public Health, The University of Hong Kong, Hong Kong Special Administrative Region, China. zhuhch@hku.hk yguan@hku.hk. ; Biotechnology Research Group, Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia. State Key Laboratory of Emerging Infectious Diseases (The University of Hong Kong-Shenzhen Branch), Shenzhen Third People's Hospital, Shenzhen, China. Shantou University-The University of Hong Kong Joint Institute of Virology, Shantou University, Shantou, China. Centre of Influenza Research and State Key Laboratory of Emerging Infectious Diseases, School of Public Health, The University of Hong Kong, Hong Kong Special Administrative Region, China. zhuhch@hku.hk yguan@hku.hk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26678874" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Camels/*virology ; Coinfection/epidemiology/veterinary/*virology ; Coronavirus Infections/epidemiology/veterinary/*virology ; Disease Reservoirs/veterinary/*virology ; Epidemiological Monitoring ; Humans ; Middle East Respiratory Syndrome Coronavirus/classification/*genetics/*physiology ; Molecular Sequence Data ; Phylogeny ; *Recombination, Genetic ; Saudi Arabia/epidemiology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 99
    Publication Date: 2015-11-21
    Description: Eukaryotic cells coordinate growth with the availability of nutrients through the mechanistic target of rapamycin complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag guanosine triphosphatases and their regulators GATOR1 and GATOR2. Sestrin2 interacts with GATOR2 and is a leucine sensor. Here we present the 2.7 angstrom crystal structure of Sestrin2 in complex with leucine. Leucine binds through a single pocket that coordinates its charged functional groups and confers specificity for the hydrophobic side chain. A loop encloses leucine and forms a lid-latch mechanism required for binding. A structure-guided mutation in Sestrin2 that decreases its affinity for leucine leads to a concomitant increase in the leucine concentration required for mTORC1 activation in cells. These results provide a structural mechanism of amino acid sensing by the mTORC1 pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698039/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698039/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Saxton, Robert A -- Knockenhauer, Kevin E -- Wolfson, Rachel L -- Chantranupong, Lynne -- Pacold, Michael E -- Wang, Tim -- Schwartz, Thomas U -- Sabatini, David M -- AI47389/AI/NIAID NIH HHS/ -- F30 CA189333/CA/NCI NIH HHS/ -- F31 CA180271/CA/NCI NIH HHS/ -- F31 CA189437/CA/NCI NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- R01 AI047389/AI/NIAID NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01CA103866/CA/NCI NIH HHS/ -- S10 RR029205/RR/NCRR NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32GM007287/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Jan 1;351(6268):53-8. doi: 10.1126/science.aad2087. Epub 2015 Nov 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA. ; Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. ; Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA. sabatini@wi.mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26586190" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding Sites ; Crystallography, X-Ray ; HEK293 Cells ; Humans ; Leucine/*chemistry/metabolism ; Metabolic Networks and Pathways ; Molecular Sequence Data ; Multiprotein Complexes/chemistry/genetics/*metabolism ; Mutation ; Nuclear Proteins/*chemistry/metabolism ; Protein Binding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; TOR Serine-Threonine Kinases/chemistry/genetics/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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