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  • *Ecosystem  (1,983)
  • Binding Sites  (1,751)
  • Phosphorylation
  • American Association for the Advancement of Science (AAAS)  (4,042)
  • Nature Publishing Group (NPG)  (823)
  • American Meteorological Society
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  • 1
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    Phase separation of signaling molecules promotes T cell receptor signal transduction (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-04-09
    Description: Activation of various cell surface receptors triggers the reorganization of downstream signaling molecules into micrometer- or submicrometer-sized clusters. However, the functional consequences of such clustering have been unclear. We biochemically reconstituted a 12-component signaling pathway on model membranes, beginning with T cell receptor (TCR) activation and ending with actin assembly. When TCR phosphorylation was triggered, downstream signaling proteins spontaneously separated into liquid-like clusters that promoted signaling outputs both in vitro and in human Jurkat T cells. Reconstituted clusters were enriched in kinases but excluded phosphatases and enhanced actin filament assembly by recruiting and organizing actin regulators. These results demonstrate that protein phase separation can create a distinct physical and biochemical compartment that facilitates signaling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Su, Xiaolei -- Ditlev, Jonathon A -- Hui, Enfu -- Xing, Wenmin -- Banjade, Sudeep -- Okrut, Julia -- King, David S -- Taunton, Jack -- Rosen, Michael K -- Vale, Ronald D -- 5-F32-DK101188/DK/NIDDK NIH HHS/ -- F32 DK101188/DK/NIDDK NIH HHS/ -- R01 GM056322/GM/NIGMS NIH HHS/ -- R01-GM56322/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Apr 29;352(6285):595-9. doi: 10.1126/science.aad9964. Epub 2016 Apr 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, MA 02543, USA. Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA. ; Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, MA 02543, USA. Department of Biophysics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. ; HHMI Mass Spectrometry Laboratory and Department of Molecular and Cellular Biology, University of California, Berkeley, CA 94720, USA. ; Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, MA 02543, USA. Department of Biophysics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. ron.vale@ucsf.edu michael.rosen@utsouthwestern.edu. ; Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, MA 02543, USA. Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA. ron.vale@ucsf.edu michael.rosen@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27056844" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/*metabolism ; Adaptor Proteins, Signal Transducing/*metabolism ; Fluorescence Recovery After Photobleaching ; Humans ; Jurkat Cells ; Membrane Proteins/*metabolism ; Mitogen-Activated Protein Kinase Kinases ; Phosphorylation ; Polymerization ; Receptors, Antigen, T-Cell/*agonists ; Signal Transduction ; T-Lymphocytes/*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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  • 2
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    Response to Comment on "Global assessment of arbuscular mycorrhizal fungus diversity reveals very low endemism" (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-26
    Description: Bruns and Taylor argue that our finding of widespread distribution among Glomeromycota "virtual taxa" is undermined by the species definition applied. Although identifying appropriate species concepts and accessing taxonomically informative traits are challenges for microorganism biogeography, the virtual taxa represent a pragmatic classification that corresponds approximately to the species rank of classical Glomeromycota taxonomy, yet is applicable to environmental DNA.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Opik, Maarja -- Davison, John -- Moora, Mari -- Partel, Meelis -- Zobel, Martin -- New York, N.Y. -- Science. 2016 Feb 19;351(6275):826. doi: 10.1126/science.aad5495.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Botany, University of Tartu, 40 Lai Street, 51005 Tartu, Estonia. maarja.opik@ut.ee. ; Department of Botany, University of Tartu, 40 Lai Street, 51005 Tartu, Estonia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912890" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Ecosystem ; Humans ; *Mycorrhizae ; Plant Roots/*microbiology ; *Symbiosis
    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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  • 3
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    Survey of variation in human transcription factors reveals prevalent DNA binding changes (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-03-26
    Description: Sequencing of exomes and genomes has revealed abundant genetic variation affecting the coding sequences of human transcription factors (TFs), but the consequences of such variation remain largely unexplored. We developed a computational, structure-based approach to evaluate TF variants for their impact on DNA binding activity and used universal protein-binding microarrays to assay sequence-specific DNA binding activity across 41 reference and 117 variant alleles found in individuals of diverse ancestries and families with Mendelian diseases. We found 77 variants in 28 genes that affect DNA binding affinity or specificity and identified thousands of rare alleles likely to alter the DNA binding activity of human sequence-specific TFs. Our results suggest that most individuals have unique repertoires of TF DNA binding activities, which may contribute to phenotypic variation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825693/" 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/PMC4825693/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barrera, Luis A -- Vedenko, Anastasia -- Kurland, Jesse V -- Rogers, Julia M -- Gisselbrecht, Stephen S -- Rossin, Elizabeth J -- Woodard, Jaie -- Mariani, Luca -- Kock, Kian Hong -- Inukai, Sachi -- Siggers, Trevor -- Shokri, Leila -- Gordan, Raluca -- Sahni, Nidhi -- Cotsapas, Chris -- Hao, Tong -- Yi, Song -- Kellis, Manolis -- Daly, Mark J -- Vidal, Marc -- Hill, David E -- Bulyk, Martha L -- P50 HG004233/HG/NHGRI NIH HHS/ -- R01 HG003985/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2016 Mar 25;351(6280):1450-4. doi: 10.1126/science.aad2257. Epub 2016 Mar 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA. Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. ; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA. ; Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. ; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Program in Biological and Biomedical Sciences, Harvard University, Cambridge, MA 02138, USA. ; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215, USA. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. ; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. ; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. ; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. Center for Human Genetics Research and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA. ; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA. Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. Program in Biological and Biomedical Sciences, Harvard University, Cambridge, MA 02138, USA. Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215, USA. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27013732" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Binding Sites ; Computer Simulation ; DNA/*metabolism ; DNA-Binding Proteins/*genetics/metabolism ; Exome/genetics ; *Gene Expression Regulation ; Genetic Diseases, Inborn/*genetics ; Genetic Variation ; Genome, Human ; Humans ; Mutation ; Polymorphism, Single Nucleotide ; Protein Array Analysis ; Protein Binding ; Sequence Analysis, DNA ; Transcription Factors/*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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  • 4
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    2.3 A resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-01-30
    Description: p97 is a hexameric AAA+ adenosine triphosphatase (ATPase) that is an attractive target for cancer drug development. We report cryo-electron microscopy (cryo-EM) structures for adenosine diphosphate (ADP)-bound, full-length, hexameric wild-type p97 in the presence and absence of an allosteric inhibitor at resolutions of 2.3 and 2.4 angstroms, respectively. We also report cryo-EM structures (at resolutions of ~3.3, 3.2, and 3.3 angstroms, respectively) for three distinct, coexisting functional states of p97 with occupancies of zero, one, or two molecules of adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS) per protomer. A large corkscrew-like change in molecular architecture, coupled with upward displacement of the N-terminal domain, is observed only when ATPgammaS is bound to both the D1 and D2 domains of the protomer. These cryo-EM structures establish the sequence of nucleotide-driven structural changes in p97 at atomic resolution. They also enable elucidation of the binding mode of an allosteric small-molecule inhibitor to p97 and illustrate how inhibitor binding at the interface between the D1 and D2 domains prevents propagation of the conformational changes necessary for p97 function.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Banerjee, Soojay -- Bartesaghi, Alberto -- Merk, Alan -- Rao, Prashant -- Bulfer, Stacie L -- Yan, Yongzhao -- Green, Neal -- Mroczkowski, Barbara -- Neitz, R Jeffrey -- Wipf, Peter -- Falconieri, Veronica -- Deshaies, Raymond J -- Milne, Jacqueline L S -- Huryn, Donna -- Arkin, Michelle -- Subramaniam, Sriram -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Feb 19;351(6275):871-5. doi: 10.1126/science.aad7974. Epub 2016 Jan 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD 20892, USA. ; Small Molecule Discovery Center, Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, CA 94143, USA. ; University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA 15260, USA. ; Leidos Biomedical Research Inc., Frederick, MD 21702, USA. ; Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA. ; Division of Biology and Biological Engineering and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91107, USA. ; Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD 20892, USA. ss1@nih.gov.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26822609" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/chemistry ; Adenosine Triphosphatases/*antagonists & inhibitors/*chemistry ; Adenosine Triphosphate/analogs & derivatives/chemistry ; Allosteric Regulation ; Binding Sites ; Cryoelectron Microscopy ; Enzyme Inhibitors ; Humans ; Models, Molecular ; Nuclear Proteins/*antagonists & inhibitors/*chemistry ; Protein Structure, Tertiary
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
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  • 5
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    mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-26
    Description: In response to growth signals, mechanistic target of rapamycin complex 1 (mTORC1) stimulates anabolic processes underlying cell growth. We found that mTORC1 increases metabolic flux through the de novo purine synthesis pathway in various mouse and human cells, thereby influencing the nucleotide pool available for nucleic acid synthesis. mTORC1 had transcriptional effects on multiple enzymes contributing to purine synthesis, with expression of the mitochondrial tetrahydrofolate (mTHF) cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) being closely associated with mTORC1 signaling in both normal and cancer cells. MTHFD2 expression and purine synthesis were stimulated by activating transcription factor 4 (ATF4), which was activated by mTORC1 independent of its canonical induction downstream of eukaryotic initiation factor 2alpha eIF2alpha phosphorylation. Thus, mTORC1 stimulates the mTHF cycle, which contributes one-carbon units to enhance production of purine nucleotides in response to growth signals.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ben-Sahra, Issam -- Hoxhaj, Gerta -- Ricoult, Stephane J H -- Asara, John M -- Manning, Brendan D -- K99-CA194192/CA/NCI NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P01-CA120964/CA/NCI NIH HHS/ -- P30-CA006516/CA/NCI NIH HHS/ -- R01 CA181390/CA/NCI NIH HHS/ -- R01-CA181390/CA/NCI NIH HHS/ -- R35 CA197459/CA/NCI NIH HHS/ -- R35-CA197459/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2016 Feb 12;351(6274):728-33. doi: 10.1126/science.aad0489.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. ; Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. ; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. bmanning@hsph.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912861" target="_blank"〉PubMed〈/a〉
    Keywords: Activating Transcription Factor 4/genetics/metabolism ; Animals ; Eukaryotic Initiation Factor-2/metabolism ; HEK293 Cells ; Humans ; Methenyltetrahydrofolate Cyclohydrolase/genetics ; Methylenetetrahydrofolate Dehydrogenase (NADP)/genetics ; Mice ; Mitochondria/*metabolism ; Multiprotein Complexes/genetics/*metabolism ; Phosphorylation ; Protein Biosynthesis ; Purines/*biosynthesis ; TOR Serine-Threonine Kinases/genetics/*metabolism ; Tetrahydrofolates/*metabolism ; Transcription, Genetic
    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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  • 6
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    CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-06
    Description: SH3 and multiple ankyrin repeat domains 3 (SHANK3) haploinsufficiency is causative for the neurological features of Phelan-McDermid syndrome (PMDS), including a high risk of autism spectrum disorder (ASD). We used unbiased, quantitative proteomics to identify changes in the phosphoproteome of Shank3-deficient neurons. Down-regulation of protein kinase B (PKB/Akt)-mammalian target of rapamycin complex 1 (mTORC1) signaling resulted from enhanced phosphorylation and activation of serine/threonine protein phosphatase 2A (PP2A) regulatory subunit, B56beta, due to increased steady-state levels of its kinase, Cdc2-like kinase 2 (CLK2). Pharmacological and genetic activation of Akt or inhibition of CLK2 relieved synaptic deficits in Shank3-deficient and PMDS patient-derived neurons. CLK2 inhibition also restored normal sociability in a Shank3-deficient mouse model. Our study thereby provides a novel mechanistic and potentially therapeutic understanding of deregulated signaling downstream of Shank3 deficiency.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bidinosti, Michael -- Botta, Paolo -- Kruttner, Sebastian -- Proenca, Catia C -- Stoehr, Natacha -- Bernhard, Mario -- Fruh, Isabelle -- Mueller, Matthias -- Bonenfant, Debora -- Voshol, Hans -- Carbone, Walter -- Neal, Sarah J -- McTighe, Stephanie M -- Roma, Guglielmo -- Dolmetsch, Ricardo E -- Porter, Jeffrey A -- Caroni, Pico -- Bouwmeester, Tewis -- Luthi, Andreas -- Galimberti, Ivan -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1199-203. doi: 10.1126/science.aad5487. Epub 2016 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland. ; Friedrich Miescher Institute, Basel, Switzerland. ; Analytical Sciences and Imaging, Novartis Institutes for Biomedical Research, Basel, Switzerland. ; Neuroscience, Novartis Institutes for Biomedical Research, Cambridge, USA. ; Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland. ivan.galimberti@novartis.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26847545" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Autism Spectrum Disorder/*drug therapy/enzymology/genetics ; Chromosome Deletion ; Chromosome Disorders/genetics ; Chromosomes, Human, Pair 22/genetics ; Disease Models, Animal ; Down-Regulation ; Gene Knockdown Techniques ; Humans ; Insulin-Like Growth Factor I/metabolism ; Mice ; Molecular Sequence Data ; Multiprotein Complexes/metabolism ; Nerve Tissue Proteins/*genetics ; Neurons/enzymology ; Phosphorylation ; Protein Phosphatase 2/metabolism ; Protein-Serine-Threonine Kinases/*antagonists & inhibitors/metabolism ; Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism ; Proteomics ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; Rats ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism
    Print ISSN: 0036-8075
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  • 7
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    Comment on "Global assessment of arbuscular mycorrhizal fungus diversity reveals very low endemism" (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-26
    Description: Davison et al. (Reports, 28 August 2015, p. 970) claim that virtual taxa of Glomeromycota show little endemism and that endemism that exists is similar to the levels seen in plant families. We show that this is likely due to the conservative species definition rather than to any ecological pattern.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bruns, Thomas D -- Taylor, John W -- New York, N.Y. -- Science. 2016 Feb 19;351(6275):826. doi: 10.1126/science.aad4228.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Plant and Microbial Biology, 111 Koshland Hall, Berkeley, CA 94720-3102, USA. pogon@berkeley.edu. ; Department of Plant and Microbial Biology, 111 Koshland Hall, Berkeley, CA 94720-3102, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912889" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Ecosystem ; Humans ; *Mycorrhizae ; Plant Roots/*microbiology ; *Symbiosis
    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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  • 8
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    Ecology: Vegetation's responses to climate variability (2016)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2016-02-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huete, Alfredo -- England -- Nature. 2016 Mar 10;531(7593):181-2. doi: 10.1038/nature17301. Epub 2016 Feb 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Plant Functional Biology and Climate Change Cluster, University of Technology Sydney, Ultimo, New South Wales 2007, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26886792" target="_blank"〉PubMed〈/a〉
    Keywords: *Acclimatization ; *Climate Change ; *Ecosystem ; *Geographic Mapping ; *Plant Physiological Phenomena
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
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    Ocean science: The rise of Rhizaria (2016)
    Nature Publishing Group (NPG)
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    Publication Date: 2016-04-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Caron, David A -- England -- Nature. 2016 Apr 28;532(7600):444-5. doi: 10.1038/nature17892. Epub 2016 Apr 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, University of Southern California, Los Angeles, California 90089-0371, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27096370" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Aquatic Organisms/*metabolism ; *Biomass ; *Biota ; Carbon/*metabolism ; *Ecosystem ; *Oceans and Seas ; Plankton/*metabolism ; Rhizaria/*isolation & purification ; Seawater/*chemistry ; Zooplankton/*isolation & purification
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
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    Crystal structure of eukaryotic translation initiation factor 2B (2016)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2016-02-24
    Description: Eukaryotic cells restrict protein synthesis under various stress conditions, by inhibiting the eukaryotic translation initiation factor 2B (eIF2B). eIF2B is the guanine nucleotide exchange factor for eIF2, a heterotrimeric G protein consisting of alpha-, beta- and gamma-subunits. eIF2B exchanges GDP for GTP on the gamma-subunit of eIF2 (eIF2gamma), and is inhibited by stress-induced phosphorylation of eIF2alpha. eIF2B is a heterodecameric complex of two copies each of the alpha-, beta-, gamma-, delta- and epsilon-subunits; its alpha-, beta- and delta-subunits constitute the regulatory subcomplex, while the gamma- and epsilon-subunits form the catalytic subcomplex. The three-dimensional structure of the entire eIF2B complex has not been determined. Here we present the crystal structure of Schizosaccharomyces pombe eIF2B with an unprecedented subunit arrangement, in which the alpha2beta2delta2 hexameric regulatory subcomplex binds two gammaepsilon dimeric catalytic subcomplexes on its opposite sides. A structure-based in vitro analysis by a surface-scanning site-directed photo-cross-linking method identified the eIF2alpha-binding and eIF2gamma-binding interfaces, located far apart on the regulatory and catalytic subcomplexes, respectively. The eIF2gamma-binding interface is located close to the conserved 'NF motif', which is important for nucleotide exchange. A structural model was constructed for the complex of eIF2B with phosphorylated eIF2alpha, which binds to eIF2B more strongly than the unphosphorylated form. These results indicate that the eIF2alpha phosphorylation generates the 'nonproductive' eIF2-eIF2B complex, which prevents nucleotide exchange on eIF2gamma, and thus provide a structural framework for the eIF2B-mediated mechanism of stress-induced translational control.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kashiwagi, Kazuhiro -- Takahashi, Mari -- Nishimoto, Madoka -- Hiyama, Takuya B -- Higo, Toshiaki -- Umehara, Takashi -- Sakamoto, Kensaku -- Ito, Takuhiro -- Yokoyama, Shigeyuki -- England -- Nature. 2016 Mar 3;531(7592):122-5. doi: 10.1038/nature16991. Epub 2016 Feb 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. ; RIKEN Systems and Structural Biology Center, Tsurumi-ku, Yokohama 230-0045, Japan. ; RIKEN Center for Life Science Technologies, Tsurumi-ku, Yokohama 230-0045, Japan. ; RIKEN Structural Biology Laboratory, Tsurumi-ku, Yokohama 230-0045, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26901872" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Binding Sites ; Biocatalysis ; Cross-Linking Reagents/chemistry ; Crystallography, X-Ray ; Eukaryotic Initiation Factor-2B/*chemistry/metabolism ; Guanosine Diphosphate/metabolism ; Guanosine Triphosphate/metabolism ; Models, Molecular ; Phosphorylation ; Protein Binding ; Protein Biosynthesis ; Protein Structure, Quaternary ; Protein Subunits/chemistry/metabolism ; Schizosaccharomyces/*chemistry
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    Transport: Nicaragua Canal may not benefit shipping (2016)
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    Publication Date: 2016-05-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Jihong -- Liu, Xiang -- England -- Nature. 2016 May 18;533(7603):321. doi: 10.1038/533321d.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Shanghai Maritime University, China. ; Rutgers University, Piscataway, New Jersey, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27193671" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Dissent and Disputes ; *Ecosystem ; *Environmental Monitoring ; *Models, Economic ; *Transportation
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    The terrestrial biosphere as a net source of greenhouse gases to the atmosphere (2016)
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    Publication Date: 2016-03-11
    Description: The terrestrial biosphere can release or absorb the greenhouse gases, carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O), and therefore has an important role in regulating atmospheric composition and climate. Anthropogenic activities such as land-use change, agriculture and waste management have altered terrestrial biogenic greenhouse gas fluxes, and the resulting increases in methane and nitrous oxide emissions in particular can contribute to climate change. The terrestrial biogenic fluxes of individual greenhouse gases have been studied extensively, but the net biogenic greenhouse gas balance resulting from anthropogenic activities and its effect on the climate system remains uncertain. Here we use bottom-up (inventory, statistical extrapolation of local flux measurements, and process-based modelling) and top-down (atmospheric inversions) approaches to quantify the global net biogenic greenhouse gas balance between 1981 and 2010 resulting from anthropogenic activities and its effect on the climate system. We find that the cumulative warming capacity of concurrent biogenic methane and nitrous oxide emissions is a factor of about two larger than the cooling effect resulting from the global land carbon dioxide uptake from 2001 to 2010. This results in a net positive cumulative impact of the three greenhouse gases on the planetary energy budget, with a best estimate (in petagrams of CO2 equivalent per year) of 3.9 +/- 3.8 (top down) and 5.4 +/- 4.8 (bottom up) based on the GWP100 metric (global warming potential on a 100-year time horizon). Our findings suggest that a reduction in agricultural methane and nitrous oxide emissions, particularly in Southern Asia, may help mitigate climate change.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tian, Hanqin -- Lu, Chaoqun -- Ciais, Philippe -- Michalak, Anna M -- Canadell, Josep G -- Saikawa, Eri -- Huntzinger, Deborah N -- Gurney, Kevin R -- Sitch, Stephen -- Zhang, Bowen -- Yang, Jia -- Bousquet, Philippe -- Bruhwiler, Lori -- Chen, Guangsheng -- Dlugokencky, Edward -- Friedlingstein, Pierre -- Melillo, Jerry -- Pan, Shufen -- Poulter, Benjamin -- Prinn, Ronald -- Saunois, Marielle -- Schwalm, Christopher R -- Wofsy, Steven C -- England -- Nature. 2016 Mar 10;531(7593):225-8. doi: 10.1038/nature16946.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉International Center for Climate and Global Change Research, School of Forestry and Wildlife Sciences, Auburn University, Auburn, Alabama 36849, USA. ; Department of Ecology, Evolution, and Organismal Biology, Iowa State University, Iowa 50011, USA. ; Laboratoire des Sciences du Climat et de l'Environnement, 91191 Gif sur Yvette, France. ; Department of Global Ecology, Carnegie Institution for Science, Stanford, California 94305, USA. ; Global Carbon Project, CSIRO Oceans and Atmosphere Research, GPO Box 3023, Canberra, Australian Capital Territory 2601, Australia. ; Department of Environmental Sciences, Emory University, Atlanta, Georgia 30322, USA. ; School of Earth Sciences and Environmental Sustainability, Northern Arizona University, Flagstaff, Arizona 86011, USA. ; School of Life Sciences, Arizona State University, Tempe, Arizona 85287, USA. ; College of Life and Environmental Sciences, University of Exeter, Exeter EX4 4RJ, UK. ; NOAA Earth System Research Laboratory, Global Monitoring Division, Boulder, Colorado 80305, USA. ; Environmental Science Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA. ; College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter EX4 4QF, UK. ; The Ecosystems Center, Marine Biological Laboratory, Woods Hole, Massachusetts 02543, USA. ; Institute of Ecosystems and Department of Ecology, Montana State University, Bozeman, Montana 59717, USA. ; Center for Global Change Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; Woods Hole Research Center, Falmouth, Massachusetts 02540, USA. ; Department of Earth and Planetary Science, Harvard University, 29 Oxford Street, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26961656" target="_blank"〉PubMed〈/a〉
    Keywords: Agriculture/statistics & numerical data ; Asia ; Atmosphere/*chemistry ; Carbon Dioxide/analysis/*metabolism ; *Ecosystem ; Global Warming/prevention & control/*statistics & numerical data ; Greenhouse Effect/prevention & control/*statistics & numerical data ; Human Activities/statistics & numerical data ; Methane/analysis/*metabolism ; Nitrous Oxide/analysis/*metabolism
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    Restoration: avoid arbitrary baselines (2016)
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    Publication Date: 2016-05-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mehrabi, Zia -- England -- Nature. 2016 May 25;533(7604):469. doi: 10.1038/533469c.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of British Columbia, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27225111" target="_blank"〉PubMed〈/a〉
    Keywords: Conservation of Natural Resources/*methods ; *Ecosystem ; *Wilderness
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    Plankton networks driving carbon export in the oligotrophic ocean (2016)
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    Publication Date: 2016-02-11
    Description: The biological carbon pump is the process by which CO2 is transformed to organic carbon via photosynthesis, exported through sinking particles, and finally sequestered in the deep ocean. While the intensity of the pump correlates with plankton community composition, the underlying ecosystem structure driving the process remains largely uncharacterized. Here we use environmental and metagenomic data gathered during the Tara Oceans expedition to improve our understanding of carbon export in the oligotrophic ocean. We show that specific plankton communities, from the surface and deep chlorophyll maximum, correlate with carbon export at 150 m and highlight unexpected taxa such as Radiolaria and alveolate parasites, as well as Synechococcus and their phages, as lineages most strongly associated with carbon export in the subtropical, nutrient-depleted, oligotrophic ocean. Additionally, we show that the relative abundance of a few bacterial and viral genes can predict a significant fraction of the variability in carbon export in these regions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851848/" 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/PMC4851848/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guidi, Lionel -- Chaffron, Samuel -- Bittner, Lucie -- Eveillard, Damien -- Larhlimi, Abdelhalim -- Roux, Simon -- Darzi, Youssef -- Audic, Stephane -- Berline, Leo -- Brum, Jennifer R -- Coelho, Luis Pedro -- Espinoza, Julio Cesar Ignacio -- Malviya, Shruti -- Sunagawa, Shinichi -- Dimier, Celine -- Kandels-Lewis, Stefanie -- Picheral, Marc -- Poulain, Julie -- Searson, Sarah -- Tara Oceans Consortium Coordinators -- Stemmann, Lars -- Not, Fabrice -- Hingamp, Pascal -- Speich, Sabrina -- Follows, Mick -- Karp-Boss, Lee -- Boss, Emmanuel -- Ogata, Hiroyuki -- Pesant, Stephane -- Weissenbach, Jean -- Wincker, Patrick -- Acinas, Silvia G -- Bork, Peer -- de Vargas, Colomban -- Iudicone, Daniele -- Sullivan, Matthew B -- Raes, Jeroen -- Karsenti, Eric -- Bowler, Chris -- Gorsky, Gabriel -- England -- Nature. 2016 Apr 28;532(7600):465-70. doi: 10.1038/nature16942. Epub 2016 Feb 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sorbonne Universites, UPMC Universite Paris 06, CNRS, Laboratoire d'oceanographie de Villefranche (LOV), Observatoire Oceanologique, 06230 Villefranche-sur-Mer, France. ; Department of Oceanography, University of Hawaii, Honolulu, Hawaii 96822, USA. ; Department of Microbiology and Immunology, Rega Institute, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. ; Center for the Biology of Disease, VIB, Herestraat 49, 3000 Leuven, Belgium. ; Department of Applied Biological Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium. ; Sorbonne Universites, UPMC Univ Paris 06, CNRS, Institut de Biologie Paris-Seine (IBPS), Evolution Paris Seine, F-75005, Paris, France. ; Ecole Normale Superieure, PSL Research University, Institut de Biologie de l'Ecole Normale Superieure (IBENS), CNRS UMR 8197, INSERM U1024, 46 rue d'Ulm, F-75005 Paris, France. ; Sorbonne Universites, UPMC Universite Paris 06, CNRS, Laboratoire Adaptation et Diversite en Milieu Marin, Station Biologique de Roscoff, 29680 Roscoff, France. ; LINA UMR 6241, Universite de Nantes, EMN, CNRS, 44322 Nantes, France. ; Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, Arizona 85721, USA. ; Structural and Computational Biology, European Molecular Biology Laboratory, Meyerhofstr. 1, 69117 Heidelberg, Germany. ; Directors' Research European Molecular Biology Laboratory Meyerhofstr. 1, 69117 Heidelberg, Germany. ; CEA - Institut de Genomique, GENOSCOPE, 2 rue Gaston Cremieux, 91057 Evry, France. ; Aix Marseille Universite, CNRS, IGS, UMR 7256, 13288 Marseille, France. ; Department of Geosciences, Laboratoire de Meteorologie Dynamique (LMD), Ecole Normale Superieure, 24 rue Lhomond, 75231 Paris CEDEX 05, France. ; Dept of Earth, Atmospheric and Planetary Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; School of Marine Sciences, University of Maine, Orono, Maine 04469, USA. ; Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto, 611-0011, Japan. ; PANGAEA, Data Publisher for Earth and Environmental Science, University of Bremen, 28359 Bremen, Germany. ; MARUM, Center for Marine Environmental Sciences, University of Bremen, 28359 Bremen, Germany. ; CNRS, UMR 8030, CP 5706 Evry, France. ; Universite d'Evry, UMR 8030, CP 5706 Evry, France. ; Department of Marine Biology and Oceanography, Institute of Marine Sciences (ICM)-CSIC, Pg. Maritim de la Barceloneta 37-49, Barcelona E0800, Spain. ; Max-Delbruck-Centre for Molecular Medicine, 13092 Berlin, Germany. ; Stazione Zoologica Anton Dohrn, Villa Comunale, 80121 Naples, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26863193" target="_blank"〉PubMed〈/a〉
    Keywords: Aquatic Organisms/genetics/isolation & purification/*metabolism ; Carbon/*metabolism ; Chlorophyll/metabolism ; Dinoflagellida/genetics/isolation & purification/metabolism ; *Ecosystem ; Expeditions ; Genes, Bacterial ; Genes, Viral ; Geography ; Oceans and Seas ; Photosynthesis ; Plankton/genetics/isolation & purification/*metabolism ; Seawater/*chemistry/microbiology/parasitology ; Synechococcus/genetics/isolation & purification/metabolism/virology
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    Restoration: 'Garden of Eden' unrealistic (2016)
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    Publication Date: 2016-05-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Breed, Martin F -- Lowe, Andrew J -- Mortimer, Peter E -- England -- Nature. 2016 May 25;533(7604):469. doi: 10.1038/533469d.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Adelaide, Australia. ; Kunming Institute of Botany; and World Agroforestry Centre, Kunming, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27225110" target="_blank"〉PubMed〈/a〉
    Keywords: Conservation of Natural Resources/*methods ; *Ecosystem ; *Wilderness
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    Boreal and temperate trees show strong acclimation of respiration to warming (2016)
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    Publication Date: 2016-03-17
    Description: Plant respiration results in an annual flux of carbon dioxide (CO2) to the atmosphere that is six times as large as that due to the emissions from fossil fuel burning, so changes in either will impact future climate. As plant respiration responds positively to temperature, a warming world may result in additional respiratory CO2 release, and hence further atmospheric warming. Plant respiration can acclimate to altered temperatures, however, weakening the positive feedback of plant respiration to rising global air temperature, but a lack of evidence on long-term (weeks to years) acclimation to climate warming in field settings currently hinders realistic predictions of respiratory release of CO2 under future climatic conditions. Here we demonstrate strong acclimation of leaf respiration to both experimental warming and seasonal temperature variation for juveniles of ten North American tree species growing for several years in forest conditions. Plants grown and measured at 3.4 degrees C above ambient temperature increased leaf respiration by an average of 5% compared to plants grown and measured at ambient temperature; without acclimation, these increases would have been 23%. Thus, acclimation eliminated 80% of the expected increase in leaf respiration of non-acclimated plants. Acclimation of leaf respiration per degree temperature change was similar for experimental warming and seasonal temperature variation. Moreover, the observed increase in leaf respiration per degree increase in temperature was less than half as large as the average reported for previous studies, which were conducted largely over shorter time scales in laboratory settings. If such dampening effects of leaf thermal acclimation occur generally, the increase in respiration rates of terrestrial plants in response to climate warming may be less than predicted, and thus may not raise atmospheric CO2 concentrations as much as anticipated.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reich, Peter B -- Sendall, Kerrie M -- Stefanski, Artur -- Wei, Xiaorong -- Rich, Roy L -- Montgomery, Rebecca A -- England -- Nature. 2016 Mar 31;531(7596):633-6. doi: 10.1038/nature17142. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Forest Resources, University of Minnesota, Minnesota 55108, USA. ; Hawkesbury Institute for the Environment, Western Sydney University, Penrith, New South Wales 2753, Australia. ; State Key Laboratory of Soil Erosion and Dryland Farming on the Loess Plateau, Northwest A&F University, Yangling 712100, China. ; Smithsonian Environmental Research Center, Edgewater, Maryland 20137, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982730" target="_blank"〉PubMed〈/a〉
    Keywords: *Acclimatization ; Atmosphere ; Carbon Dioxide/metabolism ; Cell Respiration ; Darkness ; *Ecosystem ; Forests ; *Global Warming ; North America ; Photosynthesis ; Plant Leaves/metabolism ; Seasons ; *Temperature ; Time Factors ; Trees/classification/*metabolism
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    Synthetic cycle of the initiation module of a formylating nonribosomal peptide synthetase (2016)
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    Publication Date: 2016-01-15
    Description: Nonribosomal peptide synthetases (NRPSs) are very large proteins that produce small peptide molecules with wide-ranging biological activities, including environmentally friendly chemicals and many widely used therapeutics. NRPSs are macromolecular machines, with modular assembly-line logic, a complex catalytic cycle, moving parts and many active sites. In addition to the core domains required to link the substrates, they often include specialized tailoring domains, which introduce chemical modifications and allow the product to access a large expanse of chemical space. It is still unknown how the NRPS tailoring domains are structurally accommodated into megaenzymes or how they have adapted to function in nonribosomal peptide synthesis. Here we present a series of crystal structures of the initiation module of an antibiotic-producing NRPS, linear gramicidin synthetase. This module includes the specialized tailoring formylation domain, and states are captured that represent every major step of the assembly-line synthesis in the initiation module. The transitions between conformations are large in scale, with both the peptidyl carrier protein domain and the adenylation subdomain undergoing huge movements to transport substrate between distal active sites. The structures highlight the great versatility of NRPSs, as small domains repurpose and recycle their limited interfaces to interact with their various binding partners. Understanding tailoring domains is important if NRPSs are to be utilized in the production of novel therapeutics.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reimer, Janice M -- Aloise, Martin N -- Harrison, Paul M -- Schmeing, T Martin -- 106615/Canadian Institutes of Health Research/Canada -- England -- Nature. 2016 Jan 14;529(7585):239-42. doi: 10.1038/nature16503.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, McGill University, 3649 Promenade Sir-William-Osler, Montreal, Quebec H3G 0B1, Canada. ; Department of Biology, McGill University, 1205 Dr Penfield Avenue, Montreal, Quebec H3A 1B1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26762462" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Isomerases/chemistry/metabolism ; Anti-Bacterial Agents/biosynthesis ; Binding Sites ; *Biocatalysis ; Brevibacillus/*enzymology ; Carbohydrate Metabolism ; Carrier Proteins/chemistry/metabolism ; Catalytic Domain ; Coenzymes/metabolism ; Crystallography, X-Ray ; Gramicidin/*biosynthesis ; Hydroxymethyl and Formyl Transferases/chemistry/metabolism ; Models, Molecular ; Multienzyme Complexes/chemistry/metabolism ; Pantetheine/analogs & derivatives/metabolism ; Peptide Synthases/*chemistry/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; RNA, Transfer/chemistry/metabolism
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    Land use: A global baseline for ecosystem recovery (2016)
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    Publication Date: 2016-04-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kotiaho, Janne S -- ten Brink, Ben -- Harris, Jim -- England -- Nature. 2016 Apr 7;532(7597):37. doi: 10.1038/532037c.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Jyvaskyla, Finland. ; PBL-Netherlands Environmental Assessment Agency, The Netherlands. ; Cranfield University, Bedfordshire, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27078561" target="_blank"〉PubMed〈/a〉
    Keywords: Biodiversity ; Conservation of Natural Resources/*methods ; *Ecosystem ; Human Activities ; Reference Standards ; *Wilderness
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    Nucleotide excision repair is impaired by binding of transcription factors to DNA (2016)
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    Publication Date: 2016-04-15
    Description: Somatic mutations are the driving force of cancer genome evolution. The rate of somatic mutations appears to be greatly variable across the genome due to variations in chromatin organization, DNA accessibility and replication timing. However, other variables that may influence the mutation rate locally are unknown, such as a role for DNA-binding proteins, for example. Here we demonstrate that the rate of somatic mutations in melanomas is highly increased at active transcription factor binding sites and nucleosome embedded DNA, compared to their flanking regions. Using recently available excision-repair sequencing (XR-seq) data, we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity. Our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of DNA mutations at the protein binding sites. This finding has important implications for our understanding of mutational and DNA repair processes and in the identification of cancer driver mutations.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sabarinathan, Radhakrishnan -- Mularoni, Loris -- Deu-Pons, Jordi -- Gonzalez-Perez, Abel -- Lopez-Bigas, Nuria -- England -- Nature. 2016 Apr 14;532(7598):264-7. doi: 10.1038/nature17661.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, Doctor Aiguader 88, 08003 Barcelona, Spain. ; Institucio Catalana de Recerca i Estudis Avancats (ICREA), Passeig Lluis Companys 23, 08010 Barcelona, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27075101" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; DNA/*genetics/*metabolism ; *DNA Repair ; DNA, Neoplasm/genetics/metabolism ; DNA-Binding Proteins/*metabolism ; Gene Expression Regulation, Neoplastic/genetics ; Genome, Human/genetics ; Humans ; Lung Neoplasms/genetics ; Melanoma/*genetics ; Mutagenesis/*genetics ; *Mutation Rate ; Nucleosomes/genetics/metabolism ; Promoter Regions, Genetic/genetics ; Protein Binding ; Transcription Factors/*metabolism
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    An ID2-dependent mechanism for VHL inactivation in cancer (2016)
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    Publication Date: 2016-01-07
    Description: Mechanisms that maintain cancer stem cells are crucial to tumour progression. The ID2 protein supports cancer hallmarks including the cancer stem cell state. HIFalpha transcription factors, most notably HIF2alpha (also known as EPAS1), are expressed in and required for maintenance of cancer stem cells (CSCs). However, the pathways that are engaged by ID2 or drive HIF2alpha accumulation in CSCs have remained unclear. Here we report that DYRK1A and DYRK1B kinases phosphorylate ID2 on threonine 27 (Thr27). Hypoxia downregulates this phosphorylation via inactivation of DYRK1A and DYRK1B. The activity of these kinases is stimulated in normoxia by the oxygen-sensing prolyl hydroxylase PHD1 (also known as EGLN2). ID2 binds to the VHL ubiquitin ligase complex, displaces VHL-associated Cullin 2, and impairs HIF2alpha ubiquitylation and degradation. Phosphorylation of Thr27 of ID2 by DYRK1 blocks ID2-VHL interaction and preserves HIF2alpha ubiquitylation. In glioblastoma, ID2 positively modulates HIF2alpha activity. Conversely, elevated expression of DYRK1 phosphorylates Thr27 of ID2, leading to HIF2alpha destabilization, loss of glioma stemness, inhibition of tumour growth, and a more favourable outcome for patients with glioblastoma.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Sang Bae -- Frattini, Veronique -- Bansal, Mukesh -- Castano, Angelica M -- Sherman, Dan -- Hutchinson, Keino -- Bruce, Jeffrey N -- Califano, Andrea -- Liu, Guangchao -- Cardozo, Timothy -- Iavarone, Antonio -- Lasorella, Anna -- R01CA101644/CA/NCI NIH HHS/ -- R01CA131126/CA/NCI NIH HHS/ -- R01CA178546/CA/NCI NIH HHS/ -- R01NS061776/NS/NINDS NIH HHS/ -- England -- Nature. 2016 Jan 14;529(7585):172-7. doi: 10.1038/nature16475. Epub 2016 Jan 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cancer Genetics, Columbia University Medical Center, New York 10032, USA. ; Department of Systems Biology, Columbia University Medical Center, New York 10032, USA. ; Center for Computational Biology and Bioinformatics, Columbia University Medical Center, New York 10032, USA. ; Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York 10014, USA. ; Department of Neurosurgery, Columbia University Medical Center, New York 10032, USA. ; Department of Neurology, Columbia University Medical Center, New York 10032, USA. ; Department of Pathology, Columbia University Medical Center, New York 10032, USA. ; Department of Pediatrics, Columbia University Medical Center, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26735018" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Cell Hypoxia ; Cell Line, Tumor ; Cullin Proteins/metabolism ; Glioblastoma/*metabolism/*pathology ; Humans ; Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism ; Inhibitor of Differentiation Protein 2/*metabolism ; Male ; Mice ; Neoplastic Stem Cells/*metabolism/pathology ; Oxygen/metabolism ; Phosphorylation ; Phosphothreonine/metabolism ; Protein Binding ; Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism ; Protein-Tyrosine Kinases/antagonists & inhibitors/metabolism ; Ubiquitination ; Von Hippel-Lindau Tumor Suppressor Protein/*antagonists & inhibitors/metabolism ; Xenograft Model Antitumor Assays
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    Crystal structure of the human sigma1 receptor (2016)
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    Publication Date: 2016-04-05
    Description: The human sigma1 receptor is an enigmatic endoplasmic-reticulum-resident transmembrane protein implicated in a variety of disorders including depression, drug addiction, and neuropathic pain. Recently, an additional connection to amyotrophic lateral sclerosis has emerged from studies of human genetics and mouse models. Unlike many transmembrane receptors that belong to large, extensively studied families such as G-protein-coupled receptors or ligand-gated ion channels, the sigma1 receptor is an evolutionary isolate with no discernible similarity to any other human protein. Despite its increasingly clear importance in human physiology and disease, the molecular architecture of the sigma1 receptor and its regulation by drug-like compounds remain poorly defined. Here we report crystal structures of the human sigma1 receptor in complex with two chemically divergent ligands, PD144418 and 4-IBP. The structures reveal a trimeric architecture with a single transmembrane domain in each protomer. The carboxy-terminal domain of the receptor shows an extensive flat, hydrophobic membrane-proximal surface, suggesting an intimate association with the cytosolic surface of the endoplasmic reticulum membrane in cells. This domain includes a cupin-like beta-barrel with the ligand-binding site buried at its centre. This large, hydrophobic ligand-binding cavity shows remarkable plasticity in ligand recognition, binding the two ligands in similar positions despite dissimilar chemical structures. Taken together, these results reveal the overall architecture, oligomerization state, and molecular basis for ligand recognition by this important but poorly understood protein.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schmidt, Hayden R -- Zheng, Sanduo -- Gurpinar, Esin -- Koehl, Antoine -- Manglik, Aashish -- Kruse, Andrew C -- T32GM007226/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Apr 28;532(7600):527-30. doi: 10.1038/nature17391. Epub 2016 Apr 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27042935" target="_blank"〉PubMed〈/a〉
    Keywords: Benzamides/chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Endoplasmic Reticulum/metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Intracellular Membranes/metabolism ; Isoxazoles/chemistry/metabolism ; Ligands ; Models, Molecular ; Piperidines/chemistry/metabolism ; Protein Structure, Tertiary ; Pyridines/chemistry/metabolism ; Receptors, sigma/*chemistry/metabolism ; Substrate Specificity
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    Sensitivity of global terrestrial ecosystems to climate variability (2016)
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    Publication Date: 2016-02-18
    Description: The identification of properties that contribute to the persistence and resilience of ecosystems despite climate change constitutes a research priority of global relevance. Here we present a novel, empirical approach to assess the relative sensitivity of ecosystems to climate variability, one property of resilience that builds on theoretical modelling work recognizing that systems closer to critical thresholds respond more sensitively to external perturbations. We develop a new metric, the vegetation sensitivity index, that identifies areas sensitive to climate variability over the past 14 years. The metric uses time series data derived from the moderate-resolution imaging spectroradiometer (MODIS) enhanced vegetation index, and three climatic variables that drive vegetation productivity (air temperature, water availability and cloud cover). Underlying the analysis is an autoregressive modelling approach used to identify climate drivers of vegetation productivity on monthly timescales, in addition to regions with memory effects and reduced response rates to external forcing. We find ecologically sensitive regions with amplified responses to climate variability in the Arctic tundra, parts of the boreal forest belt, the tropical rainforest, alpine regions worldwide, steppe and prairie regions of central Asia and North and South America, the Caatinga deciduous forest in eastern South America, and eastern areas of Australia. Our study provides a quantitative methodology for assessing the relative response rate of ecosystems--be they natural or with a strong anthropogenic signature--to environmental variability, which is the first step towards addressing why some regions appear to be more sensitive than others, and what impact this has on the resilience of ecosystem service provision and human well-being.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seddon, Alistair W R -- Macias-Fauria, Marc -- Long, Peter R -- Benz, David -- Willis, Kathy J -- England -- Nature. 2016 Mar 10;531(7593):229-32. doi: 10.1038/nature16986. Epub 2016 Feb 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, University of Bergen, Allegaten 41, N-500 Bergen, Norway. ; School of Geography and the Environment, South Parks Road, University of Oxford, Oxford OX1 3QY, UK. ; Long-Term Ecology Laboratory, Biodiversity Institute, Oxford Martin School, Department of Zoology, South Parks Road, University of Oxford, Oxford OX1 3PS, UK. ; Royal Botanic Gardens, Kew, Richmond, Surrey TW9 3AB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26886790" target="_blank"〉PubMed〈/a〉
    Keywords: *Acclimatization ; Americas ; Arctic Regions ; Asia ; Australia ; *Climate Change ; *Ecosystem ; Environmental Monitoring ; *Geographic Mapping ; Human Activities ; Models, Theoretical ; *Plant Physiological Phenomena ; Rainforest ; Temperature ; Time Factors ; Trees ; Water/analysis
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    Crystal structure of a substrate-engaged SecY protein-translocation channel (2016)
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    Publication Date: 2016-03-08
    Description: Hydrophobic signal sequences target secretory polypeptides to a protein-conducting channel formed by a heterotrimeric membrane protein complex, the prokaryotic SecY or eukaryotic Sec61 complex. How signal sequences are recognized is poorly understood, particularly because they are diverse in sequence and length. Structures of the inactive channel show that the largest subunit, SecY or Sec61alpha, consists of two halves that form an hourglass-shaped pore with a constriction in the middle of the membrane and a lateral gate that faces lipid. The cytoplasmic funnel is empty, while the extracellular funnel is filled with a plug domain. In bacteria, the SecY channel associates with the translating ribosome in co-translational translocation, and with the SecA ATPase in post-translational translocation. How a translocating polypeptide inserts into the channel is uncertain, as cryo-electron microscopy structures of the active channel have a relatively low resolution (~10 A) or are of insufficient quality. Here we report a crystal structure of the active channel, assembled from SecY complex, the SecA ATPase, and a segment of a secretory protein fused into SecA. The translocating protein segment inserts into the channel as a loop, displacing the plug domain. The hydrophobic core of the signal sequence forms a helix that sits in a groove outside the lateral gate, while the following polypeptide segment intercalates into the gate. The carboxy (C)-terminal section of the polypeptide loop is located in the channel, surrounded by residues of the pore ring. Thus, during translocation, the hydrophobic segments of signal sequences, and probably bilayer-spanning domains of nascent membrane proteins, exit the lateral gate and dock at a specific site that faces the lipid phase.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855518/" 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/PMC4855518/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Long -- Park, Eunyong -- Ling, JingJing -- Ingram, Jessica -- Ploegh, Hidde -- Rapoport, Tom A -- GM052586/GM/NIGMS NIH HHS/ -- R01 GM052586/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 17;531(7594):395-9. doi: 10.1038/nature17163. Epub 2016 Mar 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Harvard Medical School, Department of Cell Biology, 240 Longwood Avenue, Boston, Massachusetts 02115, USA. ; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26950603" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/*chemistry/*metabolism ; Bacterial Proteins/*chemistry/*metabolism ; Binding Sites ; Crystallography, X-Ray ; Hydrophobic and Hydrophilic Interactions ; Lipid Bilayers/chemistry/metabolism ; Membrane Transport Proteins/*chemistry/*metabolism ; Models, Molecular ; Protein Sorting Signals ; Protein Structure, Tertiary
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    Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity (2016)
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    Publication Date: 2016-01-21
    Description: Regulatory T (Treg) cells expressing the transcription factor Foxp3 have a pivotal role in maintaining immunological self-tolerance; yet, excessive Treg cell activities suppress anti-tumour immune responses. Compared to the resting Treg (rTreg) cell phenotype in secondary lymphoid organs, Treg cells in non-lymphoid tissues exhibit an activated Treg (aTreg) cell phenotype. However, the function of aTreg cells and whether their generation can be manipulated are largely unexplored. Here we show that the transcription factor Foxo1, previously demonstrated to promote Treg cell suppression of lymphoproliferative diseases, has an unexpected function in inhibiting aTreg-cell-mediated immune tolerance in mice. We find that aTreg cells turned over at a slower rate than rTreg cells, but were not locally maintained in tissues. aTreg cell differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic localization and enhanced phosphorylation at the Akt sites. Treg-cell-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules, and impeded Treg cell homing to non-lymphoid organs, causing CD8(+) T-cell-mediated autoimmune diseases. Compared to Treg cells from healthy tissues, tumour-infiltrating Treg cells downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumour-associated Treg cells, activate effector CD8(+) T cells, and inhibit tumour growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aTreg cells that have a crucial function in suppressing CD8(+) T-cell responses; and the Foxo signalling pathway in Treg cells can be titrated to break tumour immune tolerance preferentially.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Luo, Chong T -- Liao, Will -- Dadi, Saida -- Toure, Ahmed -- Li, Ming O -- P30 CA008748/CA/NCI NIH HHS/ -- R01 AI102888-01A1/AI/NIAID NIH HHS/ -- England -- Nature. 2016 Jan 28;529(7587):532-6. doi: 10.1038/nature16486. Epub 2016 Jan 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Louis V. Gerstner Jr Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; New York Genome Center, New York, New York 10013, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26789248" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autoimmunity/*immunology ; CD8-Positive T-Lymphocytes/*immunology ; Cell Differentiation ; Cell Movement/immunology ; Down-Regulation ; Female ; Forkhead Transcription Factors/biosynthesis/genetics/*metabolism ; Immune Tolerance/*immunology ; Lymphocyte Activation ; Lymphocytes, Tumor-Infiltrating/cytology/immunology/metabolism ; Male ; Mice ; Mutation ; Neoplasms/*immunology ; Phosphorylation ; Signal Transduction/immunology ; T-Lymphocytes, Regulatory/cytology/*immunology/*metabolism ; Transcription, Genetic
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    Range management: Tibetan wildlife hemmed in (2016)
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    Publication Date: 2016-02-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ji, Weihong -- Aryal, Achyut -- Su, Junhu -- England -- Nature. 2016 Feb 4;530(7588):33. doi: 10.1038/530033c.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massey University, Auckland, New Zealand; and Gansu Agricultural University, China. ; Gansu Agricultural University, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26842048" target="_blank"〉PubMed〈/a〉
    Keywords: Agriculture/instrumentation/legislation & jurisprudence ; Animal Migration ; Animals ; Animals, Wild/genetics/*physiology ; Conservation of Natural Resources/*legislation & jurisprudence/*methods ; *Ecosystem ; Environmental Policy/*legislation & jurisprudence ; Motor Vehicles ; Railroads ; Tibet
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    Cullin-RING ubiquitin E3 ligase regulation by the COP9 signalosome (2016)
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    Publication Date: 2016-04-01
    Description: The cullin-RING ubiquitin E3 ligase (CRL) family comprises over 200 members in humans. The COP9 signalosome complex (CSN) regulates CRLs by removing their ubiquitin-like activator NEDD8. The CUL4A-RBX1-DDB1-DDB2 complex (CRL4A(DDB2)) monitors the genome for ultraviolet-light-induced DNA damage. CRL4A(DBB2) is inactive in the absence of damaged DNA and requires CSN to regulate the repair process. The structural basis of CSN binding to CRL4A(DDB2) and the principles of CSN activation are poorly understood. Here we present cryo-electron microscopy structures for CSN in complex with neddylated CRL4A ligases to 6.4 A resolution. The CSN conformers defined by cryo-electron microscopy and a novel apo-CSN crystal structure indicate an induced-fit mechanism that drives CSN activation by neddylated CRLs. We find that CSN and a substrate cannot bind simultaneously to CRL4A, favouring a deneddylated, inactive state for substrate-free CRL4 complexes. These architectural and regulatory principles appear conserved across CRL families, allowing global regulation by CSN.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cavadini, Simone -- Fischer, Eric S -- Bunker, Richard D -- Potenza, Alessandro -- Lingaraju, Gondichatnahalli M -- Goldie, Kenneth N -- Mohamed, Weaam I -- Faty, Mahamadou -- Petzold, Georg -- Beckwith, Rohan E J -- Tichkule, Ritesh B -- Hassiepen, Ulrich -- Abdulrahman, Wassim -- Pantelic, Radosav S -- Matsumoto, Syota -- Sugasawa, Kaoru -- Stahlberg, Henning -- Thoma, Nicolas H -- England -- Nature. 2016 Mar 31;531(7596):598-603. doi: 10.1038/nature17416.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland. ; University of Basel, Petersplatz 10, 4003 Basel, Switzerland. ; Department of Cancer Biology, Dana-Farber Cancer Institute, LC-4312, 360 Longwood Avenue, Boston, Massachusetts 02215, USA. ; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, 4058 Basel, Switzerland. ; Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA. ; Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus, 4056 Basel, Switzerland. ; Gatan R&D, 5974 W. Las Positas Boulevard, Pleasanton, California 94588, USA. ; Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University, Kobe 657-8501, Japan. ; Graduate School of Science, Kobe University, Kobe, 657-8501, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27029275" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Apoproteins/chemistry/metabolism/ultrastructure ; Binding Sites ; *Biocatalysis ; Carrier Proteins/chemistry/metabolism/ultrastructure ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Cullin Proteins/chemistry/metabolism/ultrastructure ; DNA Damage ; DNA-Binding Proteins/chemistry/metabolism/ultrastructure ; Humans ; Kinetics ; Models, Molecular ; Multiprotein Complexes/chemistry/*metabolism/*ultrastructure ; Peptide Hydrolases/chemistry/*metabolism/*ultrastructure ; Protein Binding ; Ubiquitination ; Ubiquitins/metabolism
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    Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53 (2016)
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    Publication Date: 2016-01-21
    Description: The p53 pro-apoptotic tumour suppressor is mutated or functionally altered in most cancers. In epithelial tumours induced by 'high-risk' mucosal human papilloma viruses, including human cervical carcinoma and a growing number of head-and-neck cancers, p53 is degraded by the viral oncoprotein E6 (ref. 2). In this process, E6 binds to a short leucine (L)-rich LxxLL consensus sequence within the cellular ubiquitin ligase E6AP. Subsequently, the E6/E6AP heterodimer recruits and degrades p53 (ref. 4). Neither E6 nor E6AP are separately able to recruit p53 (refs 3, 5), and the precise mode of assembly of E6, E6AP and p53 is unknown. Here we solve the crystal structure of a ternary complex comprising full-length human papilloma virus type 16 (HPV-16) E6, the LxxLL motif of E6AP and the core domain of p53. The LxxLL motif of E6AP renders the conformation of E6 competent for interaction with p53 by structuring a p53-binding cleft on E6. Mutagenesis of critical positions at the E6-p53 interface disrupts p53 degradation. The E6-binding site of p53 is distal from previously described DNA- and protein-binding surfaces of the core domain. This suggests that, in principle, E6 may avoid competition with cellular factors by targeting both free and bound p53 molecules. The E6/E6AP/p53 complex represents a prototype of viral hijacking of both the ubiquitin-mediated protein degradation pathway and the p53 tumour suppressor pathway. The present structure provides a framework for the design of inhibitory therapeutic strategies against oncogenesis mediated by human papilloma virus.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martinez-Zapien, Denise -- Ruiz, Francesc Xavier -- Poirson, Juline -- Mitschler, Andre -- Ramirez, Juan -- Forster, Anne -- Cousido-Siah, Alexandra -- Masson, Murielle -- Vande Pol, Scott -- Podjarny, Alberto -- Trave, Gilles -- Zanier, Katia -- R01CA134737/CA/NCI NIH HHS/ -- England -- Nature. 2016 Jan 28;529(7587):541-5. doi: 10.1038/nature16481. Epub 2016 Jan 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Equipe labellisee Ligue, Biotechnologie et signalisation cellulaire UMR 7242, Ecole Superieure de Biotechnologie de Strasbourg, Boulevard Sebastien Brant, BP 10413, F-67412 Illkirch, France. ; Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC)/INSERM U964/CNRS UMR 7104/Universite de Strasbourg, 1 rue Laurent Fries, BP 10142, F-67404 Illkirch, France. ; Department of Pathology, University of Virginia, PO Box 800904, Charlottesville, Virginia 22908-0904, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26789255" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Binding Sites ; Crystallography, X-Ray ; Human papillomavirus 16/chemistry/*metabolism/pathogenicity ; Humans ; Models, Biological ; Models, Molecular ; Molecular Sequence Data ; Mutant Proteins/chemistry/metabolism ; Oncogene Proteins, Viral/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; *Proteolysis ; Repressor Proteins/*chemistry/genetics/*metabolism ; Tumor Suppressor Protein p53/*chemistry/genetics/*metabolism ; Ubiquitin-Protein Ligases/*chemistry
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    Microbial oceanography: Viral strategies at sea (2016)
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    Publication Date: 2016-03-17
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thingstad, T Frede -- Bratbak, Gunnar -- England -- Nature. 2016 Mar 24;531(7595):454-5. doi: 10.1038/nature17303. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, University of Bergen, 5020 Bergen, Norway.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982732" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anthozoa/*virology ; *Ecosystem ; *Host-Pathogen Interactions ; Viruses/*pathogenicity
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    Structure, inhibition and regulation of two-pore channel TPC1 from Arabidopsis thaliana (2016)
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    Publication Date: 2016-03-11
    Description: Two-pore channels (TPCs) comprise a subfamily (TPC1-3) of eukaryotic voltage- and ligand-gated cation channels with two non-equivalent tandem pore-forming subunits that dimerize to form quasi-tetramers. Found in vacuolar or endolysosomal membranes, they regulate the conductance of sodium and calcium ions, intravesicular pH, trafficking and excitability. TPCs are activated by a decrease in transmembrane potential and an increase in cytosolic calcium concentrations, are inhibited by low luminal pH and calcium, and are regulated by phosphorylation. Here we report the crystal structure of TPC1 from Arabidopsis thaliana at 2.87 A resolution as a basis for understanding ion permeation, channel activation, the location of voltage-sensing domains and regulatory ion-binding sites. We determined sites of phosphorylation in the amino-terminal and carboxy-terminal domains that are positioned to allosterically modulate cytoplasmic Ca(2+) activation. One of the two voltage-sensing domains (VSD2) encodes voltage sensitivity and inhibition by luminal Ca(2+) and adopts a conformation distinct from the activated state observed in structures of other voltage-gated ion channels. The structure shows that potent pharmacophore trans-Ned-19 (ref. 17) acts allosterically by clamping the pore domains to VSD2. In animals, Ned-19 prevents infection by Ebola virus and other filoviruses, presumably by altering their fusion with the endolysosome and delivery of their contents into the cytoplasm.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863712/" 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/PMC4863712/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kintzer, Alexander F -- Stroud, Robert M -- GM24485/GM/NIGMS NIH HHS/ -- P41-GM103311/GM/NIGMS NIH HHS/ -- P41-RR001614/RR/NCRR NIH HHS/ -- P41GM103393/GM/NIGMS NIH HHS/ -- R37 GM024485/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 10;531(7593):258-62. doi: 10.1038/nature17194.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26961658" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation/drug effects ; Arabidopsis/*chemistry ; Arabidopsis Proteins/*antagonists & inhibitors/*chemistry/metabolism ; Binding Sites ; Calcium/metabolism/pharmacology ; Calcium Channels/*chemistry/metabolism ; Carbolines/metabolism/pharmacology ; Crystallography, X-Ray ; Ebolavirus/drug effects ; Endosomes/drug effects/metabolism/virology ; *Ion Channel Gating/drug effects ; Ion Transport/drug effects ; Models, Molecular ; Phosphorylation ; Piperazines/metabolism/pharmacology ; Protein Structure, Tertiary/drug effects
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    Lytic to temperate switching of viral communities (2016)
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    Publication Date: 2016-03-17
    Description: Microbial viruses can control host abundances via density-dependent lytic predator-prey dynamics. Less clear is how temperate viruses, which coexist and replicate with their host, influence microbial communities. Here we show that virus-like particles are relatively less abundant at high host densities. This suggests suppressed lysis where established models predict lytic dynamics are favoured. Meta-analysis of published viral and microbial densities showed that this trend was widespread in diverse ecosystems ranging from soil to freshwater to human lungs. Experimental manipulations showed viral densities more consistent with temperate than lytic life cycles at increasing microbial abundance. An analysis of 24 coral reef viromes showed a relative increase in the abundance of hallmark genes encoded by temperate viruses with increased microbial abundance. Based on these four lines of evidence, we propose the Piggyback-the-Winner model wherein temperate dynamics become increasingly important in ecosystems with high microbial densities; thus 'more microbes, fewer viruses'.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Knowles, B -- Silveira, C B -- Bailey, B A -- Barott, K -- Cantu, V A -- Cobian-Guemes, A G -- Coutinho, F H -- Dinsdale, E A -- Felts, B -- Furby, K A -- George, E E -- Green, K T -- Gregoracci, G B -- Haas, A F -- Haggerty, J M -- Hester, E R -- Hisakawa, N -- Kelly, L W -- Lim, Y W -- Little, M -- Luque, A -- McDole-Somera, T -- McNair, K -- de Oliveira, L S -- Quistad, S D -- Robinett, N L -- Sala, E -- Salamon, P -- Sanchez, S E -- Sandin, S -- Silva, G G Z -- Smith, J -- Sullivan, C -- Thompson, C -- Vermeij, M J A -- Youle, M -- Young, C -- Zgliczynski, B -- Brainard, R -- Edwards, R A -- Nulton, J -- Thompson, F -- Rohwer, F -- England -- Nature. 2016 Mar 24;531(7595):466-70. doi: 10.1038/nature17193. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, San Diego State University, 5500 Campanile Drive, San Diego, California 92182, USA. ; Biology Institute, Rio de Janeiro Federal University, Av. Carlos Chagas Filho 373, Rio de Janeiro, Rio de Janeiro 21941-599, Brazil. ; Department of Mathematics and Statistics, San Diego State University, 5500 Campanile Drive, San Diego, California 92182, USA. ; Hawaii Institute of Marine Biology, University of Hawaii at Manoa, 46-007 Lilipuna Road, Kaneohe, Hawaii 96744, USA. ; Computational Science Research Center, San Diego State University, 5500 Campanile Drive, San Diego, California 92182, USA. ; Rainbow Rock, Ocean View, Hawaii 96737, USA. ; Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences, Centre for Molecular and Biomolecular Informatics, 6525HP Nijmegen, The Netherlands. ; Viral Information Institute, San Diego State University, 5500 Campanile Drive, San Diego, California 92182, USA. ; Scripps Institution of Oceanography, 8622 Kennel Way, La Jolla, California 92037, USA. ; Department of Biology, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. ; Marine Sciences Department, Sao Paulo Federal University - Baixada Santista, Av. Alm. Saldanha da Gama, 89, Santos, Sao Paulo 11030-400, Brazil. ; National Geographic Society, 1145 17th St NW, Washington D.C. 20036, USA. ; CARMABI Foundation, Piscaderabaai z/n, Willemstad, Curacao, Netherlands Antilles. ; Aquatic Microbiology, Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam, 1098XH Amsterdam, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982729" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anthozoa/physiology/*virology ; Bacteriophages/pathogenicity/physiology ; Coral Reefs ; *Ecosystem ; Genes, Viral/genetics ; *Host-Pathogen Interactions ; Lysogeny ; Models, Biological ; Virulence/genetics ; Viruses/genetics/isolation & purification/*pathogenicity
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    Sequence-dependent but not sequence-specific piRNA adhesion traps mRNAs to the germ plasm (2016)
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    Publication Date: 2016-03-08
    Description: The conserved Piwi family of proteins and piwi-interacting RNAs (piRNAs) have a central role in genomic stability, which is inextricably linked to germ-cell formation, by forming Piwi ribonucleoproteins (piRNPs) that silence transposable elements. In Drosophila melanogaster and other animals, primordial germ-cell specification in the developing embryo is driven by maternal messenger RNAs and proteins that assemble into specialized messenger ribonucleoproteins (mRNPs) localized in the germ (pole) plasm at the posterior of the oocyte. Maternal piRNPs, especially those loaded on the Piwi protein Aubergine (Aub), are transmitted to the germ plasm to initiate transposon silencing in the offspring germ line. The transport of mRNAs to the oocyte by midoogenesis is an active, microtubule-dependent process; mRNAs necessary for primordial germ-cell formation are enriched in the germ plasm at late oogenesis via a diffusion and entrapment mechanism, the molecular identity of which remains unknown. Aub is a central component of germ granule RNPs, which house mRNAs in the germ plasm, and interactions between Aub and Tudor are essential for the formation of germ granules. Here we show that Aub-loaded piRNAs use partial base-pairing characteristics of Argonaute RNPs to bind mRNAs randomly in Drosophila, acting as an adhesive trap that captures mRNAs in the germ plasm, in a Tudor-dependent manner. Notably, germ plasm mRNAs in drosophilids are generally longer and more abundant than other mRNAs, suggesting that they provide more target sites for piRNAs to promote their preferential tethering in germ granules. Thus, complexes containing Tudor, Aub piRNPs and mRNAs couple piRNA inheritance with germline specification. Our findings reveal an unexpected function for piRNP complexes in mRNA trapping that may be generally relevant to the function of animal germ granules.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795963/" 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/PMC4795963/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vourekas, Anastassios -- Alexiou, Panagiotis -- Vrettos, Nicholas -- Maragkakis, Manolis -- Mourelatos, Zissimos -- GM072777/GM/NIGMS NIH HHS/ -- R01 GM072777/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Mar 17;531(7594):390-4. doi: 10.1038/nature17150. Epub 2016 Mar 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Laboratory Medicine, Division of Neuropathology, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine; PENN Genome Frontiers Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26950602" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins/metabolism ; Base Pairing ; Binding Sites ; Cytoplasm/*genetics/*metabolism ; DNA Transposable Elements/genetics ; Diffusion ; Drosophila Proteins/metabolism ; Drosophila melanogaster/cytology/*genetics/metabolism ; Female ; Male ; Membrane Transport Proteins/metabolism ; Oocytes/*cytology/metabolism ; Oogenesis ; Peptide Initiation Factors/metabolism ; RNA Interference ; *RNA Transport ; RNA, Messenger/chemistry/*genetics/metabolism ; RNA, Small Interfering/chemistry/*genetics/metabolism ; Ribonucleoproteins/metabolism ; Transcriptome/genetics
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    Ecology: Change is in the air (2016)
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    Publication Date: 2016-04-30
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rodriguez, Barbra -- England -- Nature. 2016 Apr 21;532(7599):403-4.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27127819" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological ; Animal Migration ; Animals ; Biodiversity ; Climate Change/economics/*statistics & numerical data ; Ecology/economics/manpower/*methods/*trends ; *Ecosystem ; Plants ; Research/economics/manpower/*trends ; *Research Design ; Research Personnel ; *Uncertainty ; Ursidae ; *Weather
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    Re-engineering the zinc fingers of PRDM9 reverses hybrid sterility in mice (2016)
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    Publication Date: 2016-02-04
    Description: The DNA-binding protein PRDM9 directs positioning of the double-strand breaks (DSBs) that initiate meiotic recombination in mice and humans. Prdm9 is the only mammalian speciation gene yet identified and is responsible for sterility phenotypes in male hybrids of certain mouse subspecies. To investigate PRDM9 binding and its role in fertility and meiotic recombination, we humanized the DNA-binding domain of PRDM9 in C57BL/6 mice. This change repositions DSB hotspots and completely restores fertility in male hybrids. Here we show that alteration of one Prdm9 allele impacts the behaviour of DSBs controlled by the other allele at chromosome-wide scales. These effects correlate strongly with the degree to which each PRDM9 variant binds both homologues at the DSB sites it controls. Furthermore, higher genome-wide levels of such 'symmetric' PRDM9 binding associate with increasing fertility measures, and comparisons of individual hotspots suggest binding symmetry plays a downstream role in the recombination process. These findings reveal that subspecies-specific degradation of PRDM9 binding sites by meiotic drive, which steadily increases asymmetric PRDM9 binding, has impacts beyond simply changing hotspot positions, and strongly support a direct involvement in hybrid infertility. Because such meiotic drive occurs across mammals, PRDM9 may play a wider, yet transient, role in the early stages of speciation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756437/" 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/PMC4756437/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Davies, Benjamin -- Hatton, Edouard -- Altemose, Nicolas -- Hussin, Julie G -- Pratto, Florencia -- Zhang, Gang -- Hinch, Anjali Gupta -- Moralli, Daniela -- Biggs, Daniel -- Diaz, Rebeca -- Preece, Chris -- Li, Ran -- Bitoun, Emmanuelle -- Brick, Kevin -- Green, Catherine M -- Camerini-Otero, R Daniel -- Myers, Simon R -- Donnelly, Peter -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- 095552/Z/11/Z/Wellcome Trust/United Kingdom -- 098387/Z/12/Z/Wellcome Trust/United Kingdom -- Intramural NIH HHS/ -- England -- Nature. 2016 Feb 11;530(7589):171-6. doi: 10.1038/nature16931. Epub 2016 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK. ; Department of Statistics, University of Oxford, 24-29 St. Giles', Oxford OX1 3LB, UK. ; Genetics and Biochemistry Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26840484" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Binding Sites ; Chromosome Pairing/genetics ; Chromosomes, Mammalian/genetics/metabolism ; DNA Breaks, Double-Stranded ; Female ; *Genetic Speciation ; Histone-Lysine N-Methyltransferase/*chemistry/genetics/*metabolism ; Humans ; Hybridization, Genetic/*genetics ; Infertility/*genetics ; Male ; Meiosis/genetics ; Mice ; Mice, Inbred C57BL ; Protein Binding ; *Protein Engineering ; Protein Structure, Tertiary/genetics ; Recombination, Genetic/genetics ; Zinc Fingers/*genetics
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    Environment: Curb anchor scour for green shipping (2016)
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    Publication Date: 2016-05-07
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Davis, Andrew R -- Broad, Allison -- England -- Nature. 2016 May 5;533(7601):36. doi: 10.1038/533036a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Wollongong, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27147022" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Aquatic Organisms ; Biodiversity ; Conservation of Natural Resources/*methods/trends ; *Ecosystem ; Ships/*methods
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    Government cuts: Fanning the flames of Australian wildfires (2016)
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    Publication Date: 2016-04-01
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Doherty, Tim S -- Maron, Martine -- England -- Nature. 2016 Mar 31;531(7596):580. doi: 10.1038/531580b.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Deakin University, Victoria, Australia. ; The University of Queensland, Brisbane, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27029269" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Australia ; *Ecosystem ; Endangered Species ; *Financing, Government ; *Fires/economics/statistics & numerical data ; Forests ; *Global Warming/economics/statistics & numerical data ; Leadership ; Politics ; Research/*economics/trends
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    Structural basis of cohesin cleavage by separase (2016)
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    Publication Date: 2016-03-31
    Description: Accurate chromosome segregation requires timely dissolution of chromosome cohesion after chromosomes are properly attached to the mitotic spindle. Separase is absolutely essential for cohesion dissolution in organisms from yeast to man. It cleaves the kleisin subunit of cohesin and opens the cohesin ring to allow chromosome segregation. Cohesin cleavage is spatiotemporally controlled by separase-associated regulatory proteins, including the inhibitory chaperone securin, and by phosphorylation of both the enzyme and substrates. Dysregulation of this process causes chromosome missegregation and aneuploidy, contributing to cancer and birth defects. Despite its essential functions, atomic structures of separase have not been determined. Here we report crystal structures of the separase protease domain from the thermophilic fungus Chaetomium thermophilum, alone or covalently bound to unphosphorylated and phosphorylated inhibitory peptides derived from a cohesin cleavage site. These structures reveal how separase recognizes cohesin and how cohesin phosphorylation by polo-like kinase 1 (Plk1) enhances cleavage. Consistent with a previous cellular study, mutating two securin residues in a conserved motif that partly matches the separase cleavage consensus converts securin from a separase inhibitor to a substrate. Our study establishes atomic mechanisms of substrate cleavage by separase and suggests competitive inhibition by securin.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847710/" 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/PMC4847710/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lin, Zhonghui -- Luo, Xuelian -- Yu, Hongtao -- GM107415/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Apr 7;532(7597):131-4. doi: 10.1038/nature17402. Epub 2016 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390, USA. ; Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390, USA. ; Department of Biophysics, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27027290" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding, Competitive/drug effects ; Cell Cycle Proteins/chemistry/*metabolism ; Chaetomium/*enzymology ; Chromosomal Proteins, Non-Histone/chemistry/*metabolism ; Chromosome Segregation ; Crystallography, X-Ray ; Models, Molecular ; Phosphorylation ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/metabolism ; Proteolysis ; Proto-Oncogene Proteins/metabolism ; Securin/chemistry/genetics/metabolism/pharmacology ; Separase/antagonists & inhibitors/*chemistry/*metabolism ; Structure-Activity Relationship ; Substrate Specificity/genetics
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    Universal resilience patterns in complex networks (2016)
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    Publication Date: 2016-02-19
    Description: Resilience, a system's ability to adjust its activity to retain its basic functionality when errors, failures and environmental changes occur, is a defining property of many complex systems. Despite widespread consequences for human health, the economy and the environment, events leading to loss of resilience--from cascading failures in technological systems to mass extinctions in ecological networks--are rarely predictable and are often irreversible. These limitations are rooted in a theoretical gap: the current analytical framework of resilience is designed to treat low-dimensional models with a few interacting components, and is unsuitable for multi-dimensional systems consisting of a large number of components that interact through a complex network. Here we bridge this theoretical gap by developing a set of analytical tools with which to identify the natural control and state parameters of a multi-dimensional complex system, helping us derive effective one-dimensional dynamics that accurately predict the system's resilience. The proposed analytical framework allows us systematically to separate the roles of the system's dynamics and topology, collapsing the behaviour of different networks onto a single universal resilience function. The analytical results unveil the network characteristics that can enhance or diminish resilience, offering ways to prevent the collapse of ecological, biological or economic systems, and guiding the design of technological systems resilient to both internal failures and environmental changes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gao, Jianxi -- Barzel, Baruch -- Barabasi, Albert-Laszlo -- England -- Nature. 2016 Feb 18;530(7590):307-12. doi: 10.1038/nature16948.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Complex Network Research, Department of Physics, Northeastern University, Boston, Massachusetts 02115, USA. ; Department of Mathematics, Bar-Ilan University, Ramat-Gan 52900, Israel. ; Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Harvard University, Boston, Massachusetts 02215, USA. ; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Center for Network Science, Central European University, Budapest 1051, Hungary.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26887493" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological ; *Ecosystem ; Gene Expression Regulation ; Gene Regulatory Networks/*genetics ; *Models, Biological
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    Microbiology: Exclusive networks in the sea (2015)
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    Publication Date: 2015-05-29
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Limardo, Alexander J -- Worden, Alexandra Z -- England -- Nature. 2015 Jun 4;522(7554):36-7. doi: 10.1038/nature14530. Epub 2015 May 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ocean Sciences, University of California, Santa Cruz, California 95064, USA, and at the Monterey Bay Aquarium Research Institute, Moss Landing, California. ; 1] Department of Ocean Sciences, University of California, Santa Cruz, California 95064, USA, and at the Monterey Bay Aquarium Research Institute, Moss Landing, California. [2] Canadian Institute for Advanced Research, Toronto, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26017309" target="_blank"〉PubMed〈/a〉
    Keywords: Diatoms/*metabolism/*microbiology ; *Ecosystem ; Indoleacetic Acids/*metabolism ; Phytoplankton/*metabolism/*microbiology ; Rhodobacteraceae/*metabolism
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    Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration (2015)
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    Publication Date: 2015-12-10
    Description: Epithelial regeneration is critical for barrier maintenance and organ function after intestinal injury. The intestinal stem cell (ISC) niche provides Wnt, Notch and epidermal growth factor (EGF) signals supporting Lgr5(+) crypt base columnar ISCs for normal epithelial maintenance. However, little is known about the regulation of the ISC compartment after tissue damage. Using ex vivo organoid cultures, here we show that innate lymphoid cells (ILCs), potent producers of interleukin-22 (IL-22) after intestinal injury, increase the growth of mouse small intestine organoids in an IL-22-dependent fashion. Recombinant IL-22 directly targeted ISCs, augmenting the growth of both mouse and human intestinal organoids, increasing proliferation and promoting ISC expansion. IL-22 induced STAT3 phosphorylation in Lgr5(+) ISCs, and STAT3 was crucial for both organoid formation and IL-22-mediated regeneration. Treatment with IL-22 in vivo after mouse allogeneic bone marrow transplantation enhanced the recovery of ISCs, increased epithelial regeneration and reduced intestinal pathology and mortality from graft-versus-host disease. ATOH1-deficient organoid culture demonstrated that IL-22 induced epithelial regeneration independently of the Paneth cell niche. Our findings reveal a fundamental mechanism by which the immune system is able to support the intestinal epithelium, activating ISCs to promote regeneration.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720437/" 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/PMC4720437/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lindemans, Caroline A -- Calafiore, Marco -- Mertelsmann, Anna M -- O'Connor, Margaret H -- Dudakov, Jarrod A -- Jenq, Robert R -- Velardi, Enrico -- Young, Lauren F -- Smith, Odette M -- Lawrence, Gillian -- Ivanov, Juliet A -- Fu, Ya-Yuan -- Takashima, Shuichiro -- Hua, Guoqiang -- Martin, Maria L -- O'Rourke, Kevin P -- Lo, Yuan-Hung -- Mokry, Michal -- Romera-Hernandez, Monica -- Cupedo, Tom -- Dow, Lukas E -- Nieuwenhuis, Edward E -- Shroyer, Noah F -- Liu, Chen -- Kolesnick, Richard -- van den Brink, Marcel R M -- Hanash, Alan M -- HHSN272200900059C/PHS HHS/ -- K08 HL115355/HL/NHLBI NIH HHS/ -- K08-HL115355/HL/NHLBI NIH HHS/ -- K99 CA176376/CA/NCI NIH HHS/ -- K99-CA176376/CA/NCI NIH HHS/ -- P01 CA023766/CA/NCI NIH HHS/ -- P01-CA023766/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- P30-CA008748/CA/NCI NIH HHS/ -- R01 AI080455/AI/NIAID NIH HHS/ -- R01 AI100288/AI/NIAID NIH HHS/ -- R01 AI101406/AI/NIAID NIH HHS/ -- R01 HL069929/HL/NHLBI NIH HHS/ -- R01 HL125571/HL/NHLBI NIH HHS/ -- R01-AI080455/AI/NIAID NIH HHS/ -- R01-AI100288/AI/NIAID NIH HHS/ -- R01-AI101406/AI/NIAID NIH HHS/ -- R01-HL069929/HL/NHLBI NIH HHS/ -- R01-HL125571/HL/NHLBI NIH HHS/ -- U19 AI116497/AI/NIAID NIH HHS/ -- England -- Nature. 2015 Dec 24;528(7583):560-4. doi: 10.1038/nature16460. Epub 2015 Dec 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Pediatrics, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands. ; Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Anatomy and Developmental Biology, Monash University, Clayton 3800, Australia. ; Department of Medicine, Weill Cornell Medicine, New York, New York 10021, USA. ; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Cancer Biology &Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands. ; Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida 32610, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26649819" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Epithelial Cells/*cytology/immunology/pathology ; Female ; Graft vs Host Disease/pathology ; Humans ; Immunity, Mucosal ; Interleukins/deficiency/*immunology ; Intestinal Mucosa/*cytology/immunology/pathology ; Intestine, Small/*cytology/immunology/pathology ; Mice ; Organoids/cytology/growth & development/immunology ; Paneth Cells/cytology ; Phosphorylation ; *Regeneration ; STAT3 Transcription Factor/metabolism ; Signal Transduction ; Stem Cell Niche ; Stem Cells/*cytology/*metabolism
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    Zanne et al. reply (2015)
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    Publication Date: 2015-05-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zanne, Amy E -- Tank, David C -- Cornwell, William K -- Eastman, Jonathan M -- Smith, Stephen A -- FitzJohn, Richard G -- McGlinn, Daniel J -- O'Meara, Brian C -- Moles, Angela T -- Reich, Peter B -- Royer, Dana L -- Soltis, Douglas E -- Stevens, Peter F -- Westoby, Mark -- Wright, Ian J -- Aarssen, Lonnie -- Bertin, Robert I -- Calaminus, Andre -- Govaerts, Rafael -- Hemmings, Frank -- Leishman, Michelle R -- Oleksyn, Jacek -- Soltis, Pamela S -- Swenson, Nathan G -- Warman, Laura -- Beaulieu, Jeremy M -- England -- Nature. 2015 May 21;521(7552):E6-7. doi: 10.1038/nature14394.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biological Sciences, George Washington University, Washington DC 20052, USA. [2] Center for Conservation and Sustainable Development, Missouri Botanical Garden, St Louis, Missouri 63121, USA. ; 1] Department of Biological Sciences, University of Idaho, Moscow, Idaho 83844, USA. [2] Institute for Bioinformatics and Evolutionary Studies, University of Idaho, Moscow, Idaho 83844, USA. ; 1] Department of Ecological Sciences, Systems Ecology, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands. [2] Evolution &Ecology Research Centre, School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia. ; Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan 48109, USA. ; 1] Department of Zoology and Biodiversity Research Centre, University of British Columbia, Vancouver, British Columbia V6T1Z4, Canada. [2] Department of Biological Sciences, Macquarie University, Sydney, New South Wales 2109, Australia. ; Department of Biology, College of Charleston, Charleston, South Carolina 29424, USA. ; Department of Ecology and Evolutionary Biology, University of Tennessee, Knoxville, Tennessee 37996, USA. ; Evolution &Ecology Research Centre, School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia. ; 1] Department of Forest Resources, University of Minnesota, St Paul, Minnesota 55108, USA. [2] Hawkesbury Institute for the Environment, University of Western Sydney, Penrith, New South Wales 2751, Australia. ; Department of Earth and Environmental Sciences, Wesleyan University, Middletown, Connecticut 06459, USA. ; 1] Department of Biology, University of Florida, Gainesville, Florida 32611, USA. [2] Florida Museum of Natural History, University of Florida, Gainesville, Florida 32611, USA. [3] Genetics Institute, University of Florida, Gainesville, Florida 32611, USA. ; Department of Biology, University of Missouri-St Louis, St Louis, Missouri 63121, USA. ; Department of Biological Sciences, Macquarie University, Sydney, New South Wales 2109, Australia. ; Department of Biology, Queen's University, Kingston, Ontario K7L 3N6, Canada. ; Department of Biology, College of the Holy Cross, Worcester, Massachusetts 01610, USA. ; Department of Biology, University of Florida, Gainesville, Florida 32611, USA. ; Royal Botanic Gardens, Kew, Richmond TW9 3AB, UK. ; 1] Department of Forest Resources, University of Minnesota, St Paul, Minnesota 55108, USA. [2] Polish Academy of Sciences, Institute of Dendrology, 62-035 Kornik, Poland. ; 1] Florida Museum of Natural History, University of Florida, Gainesville, Florida 32611, USA. [2] Genetics Institute, University of Florida, Gainesville, Florida 32611, USA. ; Department of Plant Biology and Ecology, Evolutionary Biology and Behavior, Program, Michigan State University, East Lansing, Michigan 48824, USA. ; 1] Evolution &Ecology Research Centre, School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia. [2] Institute of Pacific Islands Forestry, USDA Forest Service, Hilo, Hawaii 96720, USA. ; National Institute for Mathematical &Biological Synthesis, University of Tennessee, Knoxville, Tennessee 37996, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25993971" target="_blank"〉PubMed〈/a〉
    Keywords: Angiosperms/*anatomy & histology/*physiology ; *Biological Evolution ; *Cold Climate ; *Ecosystem ; *Freezing ; Xylem/*anatomy & histology
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    Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism (2015)
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    Publication Date: 2015-11-13
    Description: Neuroblastoma is a paediatric malignancy that typically arises in early childhood, and is derived from the developing sympathetic nervous system. Clinical phenotypes range from localized tumours with excellent outcomes to widely metastatic disease in which long-term survival is approximately 40% despite intensive therapy. A previous genome-wide association study identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility and oncogenic addiction to LMO1 in the tumour cells. Here we investigate the causal DNA variant at this locus and the mechanism by which it leads to neuroblastoma tumorigenesis. We first imputed all possible genotypes across the LMO1 locus and then mapped highly associated single nucleotide polymorphism (SNPs) to areas of chromatin accessibility, evolutionary conservation and transcription factor binding sites. We show that SNP rs2168101 G〉T is the most highly associated variant (combined P = 7.47 x 10(-29), odds ratio 0.65, 95% confidence interval 0.60-0.70), and resides in a super-enhancer defined by extensive acetylation of histone H3 lysine 27 within the first intron of LMO1. The ancestral G allele that is associated with tumour formation resides in a conserved GATA transcription factor binding motif. We show that the newly evolved protective TATA allele is associated with decreased total LMO1 expression (P = 0.028) in neuroblastoma primary tumours, and ablates GATA3 binding (P 〈 0.0001). We demonstrate allelic imbalance favouring the G-containing strand in tumours heterozygous for this SNP, as demonstrated both by RNA sequencing (P 〈 0.0001) and reporter assays (P = 0.002). These findings indicate that a recently evolved polymorphism within a super-enhancer element in the first intron of LMO1 influences neuroblastoma susceptibility through differential GATA transcription factor binding and direct modulation of LMO1 expression in cis, and this leads to an oncogenic dependency in tumour cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775078/" 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/PMC4775078/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Oldridge, Derek A -- Wood, Andrew C -- Weichert-Leahey, Nina -- Crimmins, Ian -- Sussman, Robyn -- Winter, Cynthia -- McDaniel, Lee D -- Diamond, Maura -- Hart, Lori S -- Zhu, Shizhen -- Durbin, Adam D -- Abraham, Brian J -- Anders, Lars -- Tian, Lifeng -- Zhang, Shile -- Wei, Jun S -- Khan, Javed -- Bramlett, Kelli -- Rahman, Nazneen -- Capasso, Mario -- Iolascon, Achille -- Gerhard, Daniela S -- Guidry Auvil, Jaime M -- Young, Richard A -- Hakonarson, Hakon -- Diskin, Sharon J -- Look, A Thomas -- Maris, John M -- 100210/Wellcome Trust/United Kingdom -- 100210/Z/12/Z/Wellcome Trust/United Kingdom -- 1K99CA178189/CA/NCI NIH HHS/ -- R00-CA151869/CA/NCI NIH HHS/ -- R01 CA124709/CA/NCI NIH HHS/ -- R01 CA180692/CA/NCI NIH HHS/ -- R01-CA109901/CA/NCI NIH HHS/ -- R01-CA124709/CA/NCI NIH HHS/ -- R01-CA180692/CA/NCI NIH HHS/ -- RC1MD004418/MD/NIMHD NIH HHS/ -- T32 HG000046/HG/NHGRI NIH HHS/ -- T32-HG000046/HG/NHGRI NIH HHS/ -- England -- Nature. 2015 Dec 17;528(7582):418-21. doi: 10.1038/nature15540. Epub 2015 Nov 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. ; Medical Scientist Training Program, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Molecular Medicine and Pathology, University of Auckland, Auckland, Auckland Region 1142, New Zealand. ; Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA. ; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA. ; Whitehead Institute for Biomedical Research and MIT, Boston, Massachusetts 02142, USA. ; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. ; Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA. ; Thermo Fisher Scientific, Austin, Texas 78744, USA. ; The Institute of Cancer Research, London SM2 5NG, UK. ; University of Naples Federico II, 80131 Naples, Italy. ; CEINGE Biotecnologie Avanzate, 80131 Naples, Italy. ; Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland 20892, USA. ; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26560027" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Alleles ; Allelic Imbalance ; Binding Sites ; DNA-Binding Proteins/*genetics ; Enhancer Elements, Genetic/*genetics ; Epigenomics ; GATA3 Transcription Factor/metabolism ; Gene Expression Regulation, Neoplastic/genetics ; Genetic Predisposition to Disease/*genetics ; Genome-Wide Association Study ; Genotype ; Histones/chemistry/metabolism ; Humans ; Introns/genetics ; LIM Domain Proteins/*genetics ; Lysine/metabolism ; Neuroblastoma/*genetics ; Organ Specificity ; Polymorphism, Single Nucleotide/*genetics ; Reproducibility of Results ; Transcription Factors/*genetics
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    Ecology: Deep and complex ways to survive bleaching (2015)
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    Publication Date: 2015-02-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pandolfi, John M -- England -- Nature. 2015 Feb 5;518(7537):43-4. doi: 10.1038/nature14196. Epub 2015 Jan 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Biological Sciences and the Australian Research Council Centre of Excellence for Coral Reef Studies, University of Queensland, Brisbane, Queensland 4072, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25652993" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anthozoa/*growth & development/*physiology ; *Climate Change ; *Coral Reefs ; *Ecosystem
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    Agrochemical control of plant water use using engineered abscisic acid receptors (2015)
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    Publication Date: 2015-02-06
    Description: Rising temperatures and lessening fresh water supplies are threatening agricultural productivity and have motivated efforts to improve plant water use and drought tolerance. During water deficit, plants produce elevated levels of abscisic acid (ABA), which improves water consumption and stress tolerance by controlling guard cell aperture and other protective responses. One attractive strategy for controlling water use is to develop compounds that activate ABA receptors, but agonists approved for use have yet to be developed. In principle, an engineered ABA receptor that can be activated by an existing agrochemical could achieve this goal. Here we describe a variant of the ABA receptor PYRABACTIN RESISTANCE 1 (PYR1) that possesses nanomolar sensitivity to the agrochemical mandipropamid and demonstrate its efficacy for controlling ABA responses and drought tolerance in transgenic plants. Furthermore, crystallographic studies provide a mechanistic basis for its activity and demonstrate the relative ease with which the PYR1 ligand-binding pocket can be altered to accommodate new ligands. Thus, we have successfully repurposed an agrochemical for a new application using receptor engineering. We anticipate that this strategy will be applied to other plant receptors and represents a new avenue for crop improvement.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Park, Sang-Youl -- Peterson, Francis C -- Mosquna, Assaf -- Yao, Jin -- Volkman, Brian F -- Cutler, Sean R -- England -- Nature. 2015 Apr 23;520(7548):545-8. doi: 10.1038/nature14123. Epub 2015 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Plant Cell Biology and Department of Botany and Plant Sciences, University of California, Riverside, California 92521, USA [2] Institute for Integrative Genome Biology, Riverside, California 92521, USA. ; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25652827" target="_blank"〉PubMed〈/a〉
    Keywords: Abscisic Acid/*metabolism ; Acclimatization/drug effects ; Agrochemicals/*pharmacology ; Amides/*pharmacology ; Arabidopsis/drug effects/genetics/metabolism ; Arabidopsis Proteins/*genetics/*metabolism ; Binding Sites ; Carboxylic Acids/*pharmacology ; Crystallography, X-Ray ; Droughts ; Genetic Engineering ; Genotype ; Ligands ; Lycopersicon esculentum/drug effects/genetics/metabolism ; Membrane Transport Proteins/*genetics/*metabolism ; Models, Molecular ; Plant Transpiration/drug effects ; Plants/*drug effects/genetics/*metabolism ; Plants, Genetically Modified ; Stress, Physiological/drug effects ; Structure-Activity Relationship ; Water/*metabolism
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    Recovery potential of the world's coral reef fishes (2015)
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    Publication Date: 2015-04-10
    Description: Continuing degradation of coral reef ecosystems has generated substantial interest in how management can support reef resilience. Fishing is the primary source of diminished reef function globally, leading to widespread calls for additional marine reserves to recover fish biomass and restore key ecosystem functions. Yet there are no established baselines for determining when these conservation objectives have been met or whether alternative management strategies provide similar ecosystem benefits. Here we establish empirical conservation benchmarks and fish biomass recovery timelines against which coral reefs can be assessed and managed by studying the recovery potential of more than 800 coral reefs along an exploitation gradient. We show that resident reef fish biomass in the absence of fishing (B0) averages approximately 1,000 kg ha(-1), and that the vast majority (83%) of fished reefs are missing more than half their expected biomass, with severe consequences for key ecosystem functions such as predation. Given protection from fishing, reef fish biomass has the potential to recover within 35 years on average and less than 60 years when heavily depleted. Notably, alternative fisheries restrictions are largely (64%) successful at maintaining biomass above 50% of B0, sustaining key functions such as herbivory. Our results demonstrate that crucial ecosystem functions can be maintained through a range of fisheries restrictions, allowing coral reef managers to develop recovery plans that meet conservation and livelihood objectives in areas where marine reserves are not socially or politically feasible solutions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉MacNeil, M Aaron -- Graham, Nicholas A J -- Cinner, Joshua E -- Wilson, Shaun K -- Williams, Ivor D -- Maina, Joseph -- Newman, Steven -- Friedlander, Alan M -- Jupiter, Stacy -- Polunin, Nicholas V C -- McClanahan, Tim R -- England -- Nature. 2015 Apr 16;520(7547):341-4. doi: 10.1038/nature14358. Epub 2015 Apr 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Australian Institute of Marine Science, PMB 3 Townsville MC, Townsville, Queensland 4810, Australia [2] Department of Mathematics and Statistics, Dalhousie University, Halifax, Nova Scotia B3H 3J5, Canada [3] Australian Research Council Centre of Excellence for Coral Reef Studies, James Cook University, Townsville, Queensland 4811, Australia. ; Australian Research Council Centre of Excellence for Coral Reef Studies, James Cook University, Townsville, Queensland 4811, Australia. ; 1] Department of Parks and Wildlife, Kensington, Perth, Western Australia 6151, Australia [2] Oceans Institute, University of Western Australia, Crawley, Western Australia 6009, Australia. ; Coral Reef Ecosystems Division, NOAA Pacific Islands Fisheries Science Center, Honolulu, Hawaii 96818, USA. ; 1] Australian Research Council Centre of Excellence for Environmental Decisions (CEED), University of Queensland, Brisbane, St Lucia, Queensland 4074, Australia [2] Wildlife Conservation Society, Marine Programs, Bronx, New York 10460, USA. ; School of Marine Science and Technology, Newcastle University, Newcastle upon Tyne NE1 7RU, UK. ; 1] Fisheries Ecology Research Lab, Department of Biology, University of Hawaii, Honolulu, Hawaii 96822, USA [2] Pristine Seas-National Geographic, Washington DC 20036, USA. ; Wildlife Conservation Society, Marine Programs, Bronx, New York 10460, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25855298" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biodiversity ; Biomass ; Conservation of Natural Resources/*methods/statistics & numerical data/*trends ; *Coral Reefs ; *Ecosystem ; Fisheries/*methods/standards/*statistics & numerical data ; Fishes/*physiology ; Herbivory ; Population Dynamics ; Predatory Behavior ; Time Factors
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    Environment: phosphate mining risks atoll culture (2015)
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    Publication Date: 2015-06-13
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Magnan, Alexandre -- Duvat, Virginie -- England -- Nature. 2015 Jun 11;522(7555):156. doi: 10.1038/522156b.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Sustainable Development and International Relations (IDDRI), Sciences Po, Paris, France. ; Littoral, Environment and Societies Research Unit (LIENSs, UMR 7266), University of La Rochelle and CNRS, La Rochelle, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26062500" target="_blank"〉PubMed〈/a〉
    Keywords: Agriculture ; Animals ; Anthozoa ; *Ecosystem ; Fisheries ; Mining/*legislation & jurisprudence ; Pacific Ocean ; Phosphates/*isolation & purification ; Polynesia
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    Structure of the human 80S ribosome (2015)
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    Publication Date: 2015-04-23
    Description: Ribosomes are translational machineries that catalyse protein synthesis. Ribosome structures from various species are known at the atomic level, but obtaining the structure of the human ribosome has remained a challenge; efforts to address this would be highly relevant with regard to human diseases. Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 A, reaching 2.9 A resolution in the most stable regions. It provides unprecedented insights into ribosomal RNA entities and amino acid side chains, notably of the transfer RNA binding sites and specific molecular interactions with the exit site tRNA. It reveals atomic details of the subunit interface, which is seen to remodel strongly upon rotational movements of the ribosomal subunits. Furthermore, the structure paves the way for analysing antibiotic side effects and diseases associated with deregulated protein synthesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Khatter, Heena -- Myasnikov, Alexander G -- Natchiar, S Kundhavai -- Klaholz, Bruno P -- England -- Nature. 2015 Apr 30;520(7549):640-5. doi: 10.1038/nature14427. Epub 2015 Apr 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Centre for Integrative Biology (CBI), Department of Integrated Structural Biology, IGBMC (Institute of Genetics and of Molecular and Cellular Biology), 1 rue Laurent Fries, 67404 Illkirch, France [2] Centre National de la Recherche Scientifique (CNRS), UMR 7104, 67404 Illkirch, France [3] Institut National de la Sante et de la Recherche Medicale (INSERM) U964, 67404 Illkirch, France [4] Universite de Strasbourg, 67081 Strasbourg, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25901680" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; *Cryoelectron Microscopy ; Electrons ; Humans ; Models, Molecular ; RNA, Ribosomal/chemistry/metabolism/ultrastructure ; RNA, Transfer/chemistry/metabolism/ultrastructure ; Ribosomal Proteins/chemistry/metabolism/ultrastructure ; Ribosome Subunits/chemistry/metabolism/ultrastructure ; Ribosomes/*chemistry/metabolism/*ultrastructure
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    Two disparate ligand-binding sites in the human P2Y1 receptor (2015)
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    Publication Date: 2015-03-31
    Description: In response to adenosine 5'-diphosphate, the P2Y1 receptor (P2Y1R) facilitates platelet aggregation, and thus serves as an important antithrombotic drug target. Here we report the crystal structures of the human P2Y1R in complex with a nucleotide antagonist MRS2500 at 2.7 A resolution, and with a non-nucleotide antagonist BPTU at 2.2 A resolution. The structures reveal two distinct ligand-binding sites, providing atomic details of P2Y1R's unique ligand-binding modes. MRS2500 recognizes a binding site within the seven transmembrane bundle of P2Y1R, which is different in shape and location from the nucleotide binding site in the previously determined structure of P2Y12R, representative of another P2YR subfamily. BPTU binds to an allosteric pocket on the external receptor interface with the lipid bilayer, making it the first structurally characterized selective G-protein-coupled receptor (GPCR) ligand located entirely outside of the helical bundle. These high-resolution insights into P2Y1R should enable discovery of new orthosteric and allosteric antithrombotic drugs with reduced adverse effects.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408927/" 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/PMC4408927/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Dandan -- Gao, Zhan-Guo -- Zhang, Kaihua -- Kiselev, Evgeny -- Crane, Steven -- Wang, Jiang -- Paoletta, Silvia -- Yi, Cuiying -- Ma, Limin -- Zhang, Wenru -- Han, Gye Won -- Liu, Hong -- Cherezov, Vadim -- Katritch, Vsevolod -- Jiang, Hualiang -- Stevens, Raymond C -- Jacobson, Kenneth A -- Zhao, Qiang -- Wu, Beili -- U54 GM094618/GM/NIGMS NIH HHS/ -- U54GM094618/GM/NIGMS NIH HHS/ -- Z01 DK031116-21/Intramural NIH HHS/ -- Z01DK031116-26/DK/NIDDK NIH HHS/ -- ZIA DK031116-26/Intramural NIH HHS/ -- England -- Nature. 2015 Apr 16;520(7547):317-21. doi: 10.1038/nature14287. Epub 2015 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Bridge Institute, Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA. ; Bridge Institute, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA. ; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; 1] Bridge Institute, Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA [2] Bridge Institute, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA [3] iHuman Institute, ShanghaiTech University, 99 Haike Road, Pudong, Shanghai 201203, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25822790" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/analogs & derivatives/chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Deoxyadenine Nucleotides/*chemistry/*metabolism/pharmacology ; Humans ; Ligands ; Models, Molecular ; Molecular Conformation ; Purinergic P2Y Receptor Antagonists/*chemistry/metabolism/pharmacology ; Receptors, Purinergic P2Y1/*chemistry/*metabolism ; Thionucleotides/chemistry/metabolism ; Uracil/*analogs & derivatives/chemistry/metabolism/pharmacology
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    Conformational dynamics of a class C G-protein-coupled receptor (2015)
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    Publication Date: 2015-08-11
    Description: G-protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors in eukaryotes. Crystal structures have provided insight into GPCR interactions with ligands and G proteins, but our understanding of the conformational dynamics of activation is incomplete. Metabotropic glutamate receptors (mGluRs) are dimeric class C GPCRs that modulate neuronal excitability, synaptic plasticity, and serve as drug targets for neurological disorders. A 'clamshell' ligand-binding domain (LBD), which contains the ligand-binding site, is coupled to the transmembrane domain via a cysteine-rich domain, and LBD closure seems to be the first step in activation. Crystal structures of isolated mGluR LBD dimers led to the suggestion that activation also involves a reorientation of the dimer interface from a 'relaxed' to an 'active' state, but the relationship between ligand binding, LBD closure and dimer interface rearrangement in activation remains unclear. Here we use single-molecule fluorescence resonance energy transfer to probe the activation mechanism of full-length mammalian group II mGluRs. We show that the LBDs interconvert between three conformations: resting, activated and a short-lived intermediate state. Orthosteric agonists induce transitions between these conformational states, with efficacy determined by occupancy of the active conformation. Unlike mGluR2, mGluR3 displays basal dynamics, which are Ca(2+)-dependent and lead to basal protein activation. Our results support a general mechanism for the activation of mGluRs in which agonist binding induces closure of the LBDs, followed by dimer interface reorientation. Our experimental strategy should be widely applicable to study conformational dynamics in GPCRs and other membrane proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597782/" 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/PMC4597782/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vafabakhsh, Reza -- Levitz, Joshua -- Isacoff, Ehud Y -- 2PN2EY018241/EY/NEI NIH HHS/ -- PN2 EY018241/EY/NEI NIH HHS/ -- England -- Nature. 2015 Aug 27;524(7566):497-501. doi: 10.1038/nature14679. Epub 2015 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA. ; Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720, USA. ; Physical Bioscience Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26258295" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Drug Partial Agonism ; *Fluorescence Resonance Energy Transfer ; Humans ; Ligands ; Models, Biological ; Models, Molecular ; Protein Binding ; Protein Conformation ; Rats ; Receptors, Metabotropic Glutamate/*chemistry/*classification/genetics/metabolism
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    Structure of the TRPA1 ion channel suggests regulatory mechanisms (2015)
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    Publication Date: 2015-04-10
    Description: The TRPA1 ion channel (also known as the wasabi receptor) is a detector of noxious chemical agents encountered in our environment or produced endogenously during tissue injury or drug metabolism. These include a broad class of electrophiles that activate the channel through covalent protein modification. TRPA1 antagonists hold potential for treating neurogenic inflammatory conditions provoked or exacerbated by irritant exposure. Despite compelling reasons to understand TRPA1 function, structural mechanisms underlying channel regulation remain obscure. Here we use single-particle electron cryo- microscopy to determine the structure of full-length human TRPA1 to approximately 4 A resolution in the presence of pharmacophores, including a potent antagonist. Several unexpected features are revealed, including an extensive coiled-coil assembly domain stabilized by polyphosphate co-factors and a highly integrated nexus that converges on an unpredicted transient receptor potential (TRP)-like allosteric domain. These findings provide new insights into the mechanisms of TRPA1 regulation, and establish a blueprint for structure-based design of analgesic and anti-inflammatory agents.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409540/" 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/PMC4409540/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Paulsen, Candice E -- Armache, Jean-Paul -- Gao, Yuan -- Cheng, Yifan -- Julius, David -- R01 GM098672/GM/NIGMS NIH HHS/ -- R01 NS055299/NS/NINDS NIH HHS/ -- R01GM098672/GM/NIGMS NIH HHS/ -- R01NS055299/NS/NINDS NIH HHS/ -- T32 GM008284/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Apr 23;520(7548):511-7. doi: 10.1038/nature14367. Epub 2015 Apr 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology, University of California, San Francisco, California 94158-2517, USA. ; Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2517, USA. ; 1] Department of Physiology, University of California, San Francisco, California 94158-2517, USA [2] Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2517, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25855297" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Analgesics ; Ankyrin Repeat ; Anti-Inflammatory Agents ; Binding Sites ; Calcium Channels/*chemistry/metabolism/*ultrastructure ; *Cryoelectron Microscopy ; Cytosol/metabolism ; Humans ; Models, Molecular ; Nerve Tissue Proteins/antagonists & ; inhibitors/*chemistry/metabolism/*ultrastructure ; Polyphosphates/metabolism/pharmacology ; Protein Stability/drug effects ; Protein Subunits/chemistry/metabolism ; Structure-Activity Relationship ; Transient Receptor Potential Channels/antagonists & ; inhibitors/*chemistry/metabolism/*ultrastructure
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    Structure of mammalian eIF3 in the context of the 43S preinitiation complex (2015)
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    Publication Date: 2015-09-08
    Description: During eukaryotic translation initiation, 43S complexes, comprising a 40S ribosomal subunit, initiator transfer RNA and initiation factors (eIF) 2, 3, 1 and 1A, attach to the 5'-terminal region of messenger RNA and scan along it to the initiation codon. Scanning on structured mRNAs also requires the DExH-box protein DHX29. Mammalian eIF3 contains 13 subunits and participates in nearly all steps of translation initiation. Eight subunits having PCI (proteasome, COP9 signalosome, eIF3) or MPN (Mpr1, Pad1, amino-terminal) domains constitute the structural core of eIF3, to which five peripheral subunits are flexibly linked. Here we present a cryo-electron microscopy structure of eIF3 in the context of the DHX29-bound 43S complex, showing the PCI/MPN core at approximately 6 A resolution. It reveals the organization of the individual subunits and their interactions with components of the 43S complex. We were able to build near-complete polyalanine-level models of the eIF3 PCI/MPN core and of two peripheral subunits. The implications for understanding mRNA ribosomal attachment and scanning are discussed.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719162/" 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/PMC4719162/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉des Georges, Amedee -- Dhote, Vidya -- Kuhn, Lauriane -- Hellen, Christopher U T -- Pestova, Tatyana V -- Frank, Joachim -- Hashem, Yaser -- R01 GM029169/GM/NIGMS NIH HHS/ -- R01 GM059660/GM/NIGMS NIH HHS/ -- R01 GM29169/GM/NIGMS NIH HHS/ -- R01 GM59660/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Sep 24;525(7570):491-5. doi: 10.1038/nature14891. Epub 2015 Sep 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉HHMI, Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA. ; Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York 11203, USA. ; CNRS, Proteomic Platform Strasbourg - Esplanade, Strasbourg 67084, France. ; Department of Biological Sciences, Columbia University, New York, New York 10032, USA. ; CNRS, Architecture et Reactivite de l'ARN, Universite de Strasbourg, Strasbourg 67084, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26344199" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Codon, Initiator/genetics ; Cryoelectron Microscopy ; Eukaryotic Initiation Factor-2/chemistry/metabolism ; Eukaryotic Initiation Factor-3/*chemistry/*metabolism ; Humans ; Models, Molecular ; Multiprotein Complexes/*chemistry/*metabolism ; *Peptide Chain Initiation, Translational ; Peptide Initiation Factors/metabolism ; Protein Structure, Secondary ; Protein Subunits/chemistry/metabolism ; RNA Helicases/chemistry/metabolism ; RNA, Messenger/genetics/metabolism ; RNA, Transfer, Met/metabolism ; Ribosome Subunits, Small, Eukaryotic/chemistry/metabolism ; Ribosomes/*chemistry/*metabolism
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    Crystal structure of the V(D)J recombinase RAG1-RAG2 (2015)
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    Publication Date: 2015-02-25
    Description: V(D)J recombination in the vertebrate immune system generates a highly diverse population of immunoglobulins and T-cell receptors by combinatorial joining of segments of coding DNA. The RAG1-RAG2 protein complex initiates this site-specific recombination by cutting DNA at specific sites flanking the coding segments. Here we report the crystal structure of the mouse RAG1-RAG2 complex at 3.2 A resolution. The 230-kilodalton RAG1-RAG2 heterotetramer is 'Y-shaped', with the amino-terminal domains of the two RAG1 chains forming an intertwined stalk. Each RAG1-RAG2 heterodimer composes one arm of the 'Y', with the active site in the middle and RAG2 at its tip. The RAG1-RAG2 structure rationalizes more than 60 mutations identified in immunodeficient patients, as well as a large body of genetic and biochemical data. The architectural similarity between RAG1 and the hairpin-forming transposases Hermes and Tn5 suggests the evolutionary conservation of these DNA rearrangements.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342785/" 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/PMC4342785/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Min-Sung -- Lapkouski, Mikalai -- Yang, Wei -- Gellert, Martin -- Z01 DK036147-01/Intramural NIH HHS/ -- Z01 DK036147-02/Intramural NIH HHS/ -- Z01 DK036167-01/Intramural NIH HHS/ -- Z01 DK036167-02/Intramural NIH HHS/ -- ZIA DK036147-03/Intramural NIH HHS/ -- ZIA DK036147-04/Intramural NIH HHS/ -- ZIA DK036147-05/Intramural NIH HHS/ -- ZIA DK036147-06/Intramural NIH HHS/ -- ZIA DK036147-07/Intramural NIH HHS/ -- ZIA DK036147-08/Intramural NIH HHS/ -- ZIA DK036167-03/Intramural NIH HHS/ -- ZIA DK036167-04/Intramural NIH HHS/ -- ZIA DK036167-05/Intramural NIH HHS/ -- ZIA DK036167-06/Intramural NIH HHS/ -- ZIA DK036167-07/Intramural NIH HHS/ -- England -- Nature. 2015 Feb 26;518(7540):507-11. doi: 10.1038/nature14174. Epub 2015 Feb 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Biology, NIDDK, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25707801" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; DNA-Binding Proteins/*chemistry/genetics/metabolism ; Homeodomain Proteins/*chemistry/genetics/metabolism ; Humans ; Mice ; Models, Molecular ; Mutation/genetics ; Protein Multimerization ; Protein Structure, Quaternary ; Severe Combined Immunodeficiency/genetics ; Transposases/chemistry ; VDJ Recombinases/*chemistry/metabolism ; X-Linked Combined Immunodeficiency Diseases/genetics
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    Predicting climate-driven regime shifts versus rebound potential in coral reefs (2015)
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    Publication Date: 2015-01-22
    Description: Climate-induced coral bleaching is among the greatest current threats to coral reefs, causing widespread loss of live coral cover. Conditions under which reefs bounce back from bleaching events or shift from coral to algal dominance are unknown, making it difficult to predict and plan for differing reef responses under climate change. Here we document and predict long-term reef responses to a major climate-induced coral bleaching event that caused unprecedented region-wide mortality of Indo-Pacific corals. Following loss of 〉90% live coral cover, 12 of 21 reefs recovered towards pre-disturbance live coral states, while nine reefs underwent regime shifts to fleshy macroalgae. Functional diversity of associated reef fish communities shifted substantially following bleaching, returning towards pre-disturbance structure on recovering reefs, while becoming progressively altered on regime shifting reefs. We identified threshold values for a range of factors that accurately predicted ecosystem response to the bleaching event. Recovery was favoured when reefs were structurally complex and in deeper water, when density of juvenile corals and herbivorous fishes was relatively high and when nutrient loads were low. Whether reefs were inside no-take marine reserves had no bearing on ecosystem trajectory. Although conditions governing regime shift or recovery dynamics were diverse, pre-disturbance quantification of simple factors such as structural complexity and water depth accurately predicted ecosystem trajectories. These findings foreshadow the likely divergent but predictable outcomes for reef ecosystems in response to climate change, thus guiding improved management and adaptation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Graham, Nicholas A J -- Jennings, Simon -- MacNeil, M Aaron -- Mouillot, David -- Wilson, Shaun K -- England -- Nature. 2015 Feb 5;518(7537):94-7. doi: 10.1038/nature14140. Epub 2015 Jan 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Australian Research Council Centre of Excellence for Coral Reef Studies, James Cook University, Townsville, Queensland 4811 Australia. ; 1] Centre for Environment, Fisheries and Aquaculture Science, Pakefield Road, Lowestoft NR33 OHT, UK [2] School of Environmental Sciences, University of East Anglia, Norwich NR4 7TJ, UK. ; 1] Australian Research Council Centre of Excellence for Coral Reef Studies, James Cook University, Townsville, Queensland 4811 Australia [2] Australian Institute of Marine Science, PMB 3 Townsville MC, Townsville, Queensland 4810, Australia. ; 1] Australian Research Council Centre of Excellence for Coral Reef Studies, James Cook University, Townsville, Queensland 4811 Australia [2] ECOSYM, UMR CNRS-UM2 5119, Universite Montpellier 2, 34095 Montpellier Cedex, France. ; 1] Department of Parks and Wildlife, Kensington, Perth, Western Australia 6151, Australia [2] School of Plant Biology, Oceans Institute, University of Western Australia, Crawley, Western Australia 6009, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25607371" target="_blank"〉PubMed〈/a〉
    Keywords: Acclimatization ; Animals ; Anthozoa/*growth & development/*physiology ; Biodiversity ; *Climate Change ; *Coral Reefs ; *Ecosystem ; Fishes/physiology ; Indian Ocean ; Pacific Ocean ; Population Dynamics ; Seawater/analysis ; Seaweed/physiology ; Seychelles ; Symbiosis ; Tropical Climate
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    Climate science: The future of coastal ocean upwelling (2015)
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    Publication Date: 2015-02-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Di Lorenzo, Emanuele -- England -- Nature. 2015 Feb 19;518(7539):310-1. doi: 10.1038/518310a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Earth and Atmospheric Sciences, Georgia Institute of Technology, Atlanta, Georgia 30332-0340, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25693560" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Climate Change ; *Ecosystem ; *Water Movements
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    MAP4K4 regulates integrin-FERM binding to control endothelial cell motility (2015)
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    Publication Date: 2015-03-25
    Description: Cell migration is a stepwise process that coordinates multiple molecular machineries. Using in vitro angiogenesis screens with short interfering RNA and chemical inhibitors, we define here a MAP4K4-moesin-talin-beta1-integrin molecular pathway that promotes efficient plasma membrane retraction during endothelial cell migration. Loss of MAP4K4 decreased membrane dynamics, slowed endothelial cell migration, and impaired angiogenesis in vitro and in vivo. In migrating endothelial cells, MAP4K4 phosphorylates moesin in retracting membranes at sites of focal adhesion disassembly. Epistasis analyses indicated that moesin functions downstream of MAP4K4 to inactivate integrin by competing with talin for binding to beta1-integrin intracellular domain. Consequently, loss of moesin (encoded by the MSN gene) or MAP4K4 reduced adhesion disassembly rate in endothelial cells. Additionally, alpha5beta1-integrin blockade reversed the membrane retraction defects associated with loss of Map4k4 in vitro and in vivo. Our study uncovers a novel aspect of endothelial cell migration. Finally, loss of MAP4K4 function suppressed pathological angiogenesis in disease models, identifying MAP4K4 as a potential therapeutic target.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vitorino, Philip -- Yeung, Stacey -- Crow, Ailey -- Bakke, Jesse -- Smyczek, Tanya -- West, Kristina -- McNamara, Erin -- Eastham-Anderson, Jeffrey -- Gould, Stephen -- Harris, Seth F -- Ndubaku, Chudi -- Ye, Weilan -- England -- Nature. 2015 Mar 26;519(7544):425-30. doi: 10.1038/nature14323. Epub 2015 Mar 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Biology Department, Genentech, Inc., South San Francisco, California 94080, USA. ; Chemical Biology and Therapeutics Department, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Translational Oncology Department, Genentech, Inc., South San Francisco, California 94080, USA. ; Pathology Department, Genentech, Inc., South San Francisco, California 94080, USA. ; Structural Biology Department, Genentech, Inc., South San Francisco, California 94080, USA. ; Discovery Chemistry Department, Genentech, Inc., South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25799996" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; Antigens, CD29/chemistry/drug effects/metabolism ; Cell Membrane/drug effects/metabolism ; *Cell Movement ; Cell Shape/drug effects ; Endothelial Cells/*cytology/drug effects/*metabolism ; Epistasis, Genetic ; Focal Adhesions/metabolism ; Humans ; Integrin alpha1/drug effects/metabolism ; Integrins/drug effects/*metabolism ; Intracellular Signaling Peptides and Proteins/antagonists & ; inhibitors/deficiency/genetics/*metabolism ; Male ; Mice ; Microfilament Proteins/deficiency/genetics/metabolism ; Neovascularization, Pathologic ; Phosphorylation ; Protein Binding ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/antagonists & ; inhibitors/deficiency/genetics/*metabolism ; Talin/chemistry/metabolism
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    Finland: target for ecosystem repair is impractical (2015)
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    Publication Date: 2015-03-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kotiaho, Janne S -- England -- Nature. 2015 Mar 5;519(7541):33. doi: 10.1038/519033a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Jyvaskyla, Finland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25739622" target="_blank"〉PubMed〈/a〉
    Keywords: Biodiversity ; Conservation of Natural Resources/*methods/*statistics & numerical data ; *Ecosystem ; Finland ; Forestry/methods/statistics & numerical data ; Forests
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    Mining disaster: Restore habitats now (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-12-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Massante, Jhonny Capichoni -- England -- Nature. 2015 Dec 3;528(7580):39. doi: 10.1038/528039c.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Federal University Fluminense, Niteroi, Rio de Janeiro, Brazil.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26632581" target="_blank"〉PubMed〈/a〉
    Keywords: Biodiversity ; Cities ; *Disasters/prevention & control ; *Ecosystem ; Humans ; *Mining ; Rainforest ; Water Pollutants/*adverse effects ; Water Supply
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    Structural insights into the bacterial carbon-phosphorus lyase machinery (2015)
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    Publication Date: 2015-08-19
    Description: Phosphorus is required for all life and microorganisms can extract it from their environment through several metabolic pathways. When phosphate is in limited supply, some bacteria are able to use phosphonate compounds, which require specialized enzymatic machinery to break the stable carbon-phosphorus (C-P) bond. Despite its importance, the details of how this machinery catabolizes phosphonates remain unknown. Here we determine the crystal structure of the 240-kilodalton Escherichia coli C-P lyase core complex (PhnG-PhnH-PhnI-PhnJ; PhnGHIJ), and show that it is a two-fold symmetric hetero-octamer comprising an intertwined network of subunits with unexpected self-homologies. It contains two potential active sites that probably couple phosphonate compounds to ATP and subsequently hydrolyse the C-P bond. We map the binding site of PhnK on the complex using electron microscopy, and show that it binds to a conserved insertion domain of PhnJ. Our results provide a structural basis for understanding microbial phosphonate breakdown.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617613/" 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/PMC4617613/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seweryn, Paulina -- Van, Lan Bich -- Kjeldgaard, Morten -- Russo, Christopher J -- Passmore, Lori A -- Hove-Jensen, Bjarne -- Jochimsen, Bjarne -- Brodersen, Ditlev E -- MC_U105192715/Medical Research Council/United Kingdom -- England -- Nature. 2015 Sep 3;525(7567):68-72. doi: 10.1038/nature14683. Epub 2015 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10c, DK-8000 Aarhus C, Denmark. ; Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26280334" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Binding Sites ; Biocatalysis ; Carbon/chemistry/metabolism ; Conserved Sequence ; Crystallography, X-Ray ; Escherichia coli/*enzymology ; Escherichia coli Proteins/*chemistry/*metabolism/ultrastructure ; Hydrolysis ; Iron/chemistry/metabolism ; Lyases/*chemistry/*metabolism/ultrastructure ; Microscopy, Electron ; Models, Molecular ; Organophosphonates/metabolism ; Phosphorus/chemistry/metabolism ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Sulfur/chemistry/metabolism
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    In situ structural analysis of the human nuclear pore complex (2015)
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    Publication Date: 2015-09-30
    Description: Nuclear pore complexes are fundamental components of all eukaryotic cells that mediate nucleocytoplasmic exchange. Determining their 110-megadalton structure imposes a formidable challenge and requires in situ structural biology approaches. Of approximately 30 nucleoporins (Nups), 15 are structured and form the Y and inner-ring complexes. These two major scaffolding modules assemble in multiple copies into an eight-fold rotationally symmetric structure that fuses the inner and outer nuclear membranes to form a central channel of ~60 nm in diameter. The scaffold is decorated with transport-channel Nups that often contain phenylalanine-repeat sequences and mediate the interaction with cargo complexes. Although the architectural arrangement of parts of the Y complex has been elucidated, it is unclear how exactly it oligomerizes in situ. Here we combine cryo-electron tomography with mass spectrometry, biochemical analysis, perturbation experiments and structural modelling to generate, to our knowledge, the most comprehensive architectural model of the human nuclear pore complex to date. Our data suggest previously unknown protein interfaces across Y complexes and to inner-ring complex members. We show that the transport-channel Nup358 (also known as Ranbp2) has a previously unanticipated role in Y-complex oligomerization. Our findings blur the established boundaries between scaffold and transport-channel Nups. We conclude that, similar to coated vesicles, several copies of the same structural building block--although compositionally identical--engage in different local sets of interactions and conformations.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉von Appen, Alexander -- Kosinski, Jan -- Sparks, Lenore -- Ori, Alessandro -- DiGuilio, Amanda L -- Vollmer, Benjamin -- Mackmull, Marie-Therese -- Banterle, Niccolo -- Parca, Luca -- Kastritis, Panagiotis -- Buczak, Katarzyna -- Mosalaganti, Shyamal -- Hagen, Wim -- Andres-Pons, Amparo -- Lemke, Edward A -- Bork, Peer -- Antonin, Wolfram -- Glavy, Joseph S -- Bui, Khanh Huy -- Beck, Martin -- 1R21AG047433-01/AG/NIA NIH HHS/ -- England -- Nature. 2015 Oct 1;526(7571):140-3. doi: 10.1038/nature15381. Epub 2015 Sep 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉European Molecular Biology Laboratory, Structural and Computational Biology Unit, 69117 Heidelberg, Germany. ; Department of Chemistry, Chemical Biology and Biomedical Engineering, Stevens Institute of Technology, 507 River St., Hoboken, New Jersey 07030, USA. ; Friedrich Miescher Laboratory of the Max Planck Society, Spemannstrasse 39, 72076 Tubingen, Germany. ; Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 0C7, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26416747" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; *Cryoelectron Microscopy ; HeLa Cells ; Humans ; Mass Spectrometry ; Models, Molecular ; Molecular Chaperones/chemistry/metabolism/ultrastructure ; Nuclear Envelope/metabolism ; Nuclear Pore/*chemistry/metabolism/*ultrastructure ; Nuclear Pore Complex Proteins/*chemistry/metabolism/*ultrastructure ; Protein Conformation ; Protein Multimerization ; Protein Stability
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    Doubtful pathways to cold tolerance in plants (2015)
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    Publication Date: 2015-05-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Edwards, Erika J -- de Vos, Jurriaan M -- Donoghue, Michael J -- England -- Nature. 2015 May 21;521(7552):E5-6. doi: 10.1038/nature14393.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ecology and Evolutionary Biology, Brown University, 80 Waterman St, Box G-W, Providence, Rhodes Island 02912, USA. ; Department of Ecology and Evolutionary Biology, Yale University, PO Box 208105, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25993970" target="_blank"〉PubMed〈/a〉
    Keywords: Angiosperms/*anatomy & histology/*physiology ; *Biological Evolution ; *Cold Climate ; *Ecosystem ; *Freezing ; Xylem/*anatomy & histology
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    Regulated eukaryotic DNA replication origin firing with purified proteins (2015)
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    Publication Date: 2015-03-06
    Description: Eukaryotic cells initiate DNA replication from multiple origins, which must be tightly regulated to promote precise genome duplication in every cell cycle. To accomplish this, initiation is partitioned into two temporally discrete steps: a double hexameric minichromosome maintenance (MCM) complex is first loaded at replication origins during G1 phase, and then converted to the active CMG (Cdc45-MCM-GINS) helicase during S phase. Here we describe the reconstitution of budding yeast DNA replication initiation with 16 purified replication factors, made from 42 polypeptides. Origin-dependent initiation recapitulates regulation seen in vivo. Cyclin-dependent kinase (CDK) inhibits MCM loading by phosphorylating the origin recognition complex (ORC) and promotes CMG formation by phosphorylating Sld2 and Sld3. Dbf4-dependent kinase (DDK) promotes replication by phosphorylating MCM, and can act either before or after CDK. These experiments define the minimum complement of proteins, protein kinase substrates and co-factors required for regulated eukaryotic DNA replication.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yeeles, Joseph T P -- Deegan, Tom D -- Janska, Agnieszka -- Early, Anne -- Diffley, John F X -- Cancer Research UK/United Kingdom -- England -- Nature. 2015 Mar 26;519(7544):431-5. doi: 10.1038/nature14285. Epub 2015 Mar 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms EN6 3LD, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25739503" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Cycle Proteins/metabolism ; Cyclin-Dependent Kinases/metabolism ; *DNA Replication ; DNA-Binding Proteins/metabolism ; DNA-Directed DNA Polymerase/metabolism ; Minichromosome Maintenance Proteins/metabolism ; Multienzyme Complexes/metabolism ; Multiprotein Complexes/chemistry/metabolism ; Nuclear Proteins/metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases/metabolism ; Replication Origin/genetics/*physiology ; Replication Protein A/metabolism ; Saccharomyces cerevisiae/enzymology/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/*isolation & purification/*metabolism
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    Ecology: Recovering the potential of coral reefs (2015)
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    Publication Date: 2015-04-10
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dulvy, Nicholas K -- Kindsvater, Holly K -- England -- Nature. 2015 Apr 16;520(7547):304-5. doi: 10.1038/nature14384. Epub 2015 Apr 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25855291" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Conservation of Natural Resources/*methods/*trends ; *Coral Reefs ; *Ecosystem ; Fisheries/*methods/*statistics & numerical data ; Fishes/*physiology
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    Structure of the eukaryotic MCM complex at 3.8 A (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-07-30
    Description: DNA replication in eukaryotes is strictly regulated by several mechanisms. A central step in this replication is the assembly of the heterohexameric minichromosome maintenance (MCM2-7) helicase complex at replication origins during G1 phase as an inactive double hexamer. Here, using cryo-electron microscopy, we report a near-atomic structure of the MCM2-7 double hexamer purified from yeast G1 chromatin. Our structure shows that two single hexamers, arranged in a tilted and twisted fashion through interdigitated amino-terminal domain interactions, form a kinked central channel. Four constricted rings consisting of conserved interior beta-hairpins from the two single hexamers create a narrow passageway that tightly fits duplex DNA. This narrow passageway, reinforced by the offset of the two single hexamers at the double hexamer interface, is flanked by two pairs of gate-forming subunits, MCM2 and MCM5. These unusual features of the twisted and tilted single hexamers suggest a concerted mechanism for the melting of origin DNA that requires structural deformation of the intervening DNA.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Ningning -- Zhai, Yuanliang -- Zhang, Yixiao -- Li, Wanqiu -- Yang, Maojun -- Lei, Jianlin -- Tye, Bik-Kwoon -- Gao, Ning -- England -- Nature. 2015 Aug 13;524(7564):186-91. doi: 10.1038/nature14685. Epub 2015 Jul 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ministry of Education Key Laboratory of Protein Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; 1] Division of Life Science, Hong Kong Universityof Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China [2] Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. ; 1] Division of Life Science, Hong Kong Universityof Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China [2] Department of Molecular Biology and Genetics, College of Agriculture and Life Sciences, Cornell University, Ithaca, New York 14853, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26222030" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Cell Cycle Proteins/chemistry/metabolism/ultrastructure ; Chromatin/chemistry ; Conserved Sequence ; *Cryoelectron Microscopy ; DNA/chemistry/metabolism/ultrastructure ; DNA-Directed DNA Polymerase/chemistry/ultrastructure ; G1 Phase ; Minichromosome Maintenance Proteins/*chemistry/metabolism/*ultrastructure ; Models, Biological ; Models, Molecular ; Multienzyme Complexes/chemistry/ultrastructure ; Nucleic Acid Denaturation ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Protein Subunits/*chemistry/metabolism ; Replication Origin ; Saccharomyces cerevisiae/*chemistry/*ultrastructure ; Saccharomyces cerevisiae Proteins/chemistry/metabolism/ultrastructure
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    Sustainable development goals: Monitor ecosystem services from space (2015)
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    Publication Date: 2015-09-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cord, Anna F -- Seppelt, Ralf -- Turner, Woody -- England -- Nature. 2015 Sep 3;525(7567):33. doi: 10.1038/525033a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany. ; NASA, Washington DC, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26333459" target="_blank"〉PubMed〈/a〉
    Keywords: Biodiversity ; Biofuels/supply & distribution ; Conservation of Natural Resources/*statistics & numerical data ; Ecology/*methods ; *Ecosystem ; Environmental Monitoring/instrumentation/*methods ; *Goals ; *Spacecraft ; United Nations
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    The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1 (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-07-07
    Description: Abnormal accumulation of triglycerides in the liver, caused in part by increased de novo lipogenesis, results in non-alcoholic fatty liver disease and insulin resistance. Sterol regulatory element-binding protein 1 (SREBP1), an important transcriptional regulator of lipogenesis, is synthesized as an inactive precursor that binds to the endoplasmic reticulum (ER). In response to insulin signalling, SREBP1 is transported from the ER to the Golgi in a COPII-dependent manner, processed by proteases in the Golgi, and then shuttled to the nucleus to induce lipogenic gene expression; however, the mechanisms underlying enhanced SREBP1 activity in insulin-resistant obesity and diabetes remain unclear. Here we show in mice that CREB regulated transcription coactivator 2 (CRTC2) functions as a mediator of mTOR signalling to modulate COPII-dependent SREBP1 processing. CRTC2 competes with Sec23A, a subunit of the COPII complex, to interact with Sec31A, another COPII subunit, thus disrupting SREBP1 transport. During feeding, mTOR phosphorylates CRTC2 and attenuates its inhibitory effect on COPII-dependent SREBP1 maturation. As hepatic overexpression of an mTOR-defective CRTC2 mutant in obese mice improved the lipogenic program and insulin sensitivity, these results demonstrate how the transcriptional coactivator CRTC2 regulates mTOR-mediated lipid homeostasis in the fed state and in obesity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Han, Jinbo -- Li, Erwei -- Chen, Liqun -- Zhang, Yuanyuan -- Wei, Fangchao -- Liu, Jieyuan -- Deng, Haiteng -- Wang, Yiguo -- England -- Nature. 2015 Aug 13;524(7564):243-6. doi: 10.1038/nature14557. Epub 2015 Jul 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; Proteomics Facility, School of Life Sciences, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26147081" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding, Competitive ; COP-Coated Vesicles/chemistry/metabolism ; Homeostasis ; Insulin Resistance ; *Lipid Metabolism ; Lipogenesis ; Liver/*metabolism ; Male ; Mice ; Mice, Obese ; Obesity/metabolism ; Phosphorylation ; Protein Processing, Post-Translational ; Protein Transport ; Signal Transduction ; Sterol Regulatory Element Binding Protein 1/*metabolism ; TOR Serine-Threonine Kinases/metabolism ; Transcription Factors/deficiency/genetics/*metabolism ; Vesicular Transport Proteins/metabolism
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    Repeated ER-endosome contacts promote endosome translocation and neurite outgrowth (2015)
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    Publication Date: 2015-04-10
    Description: The main organelles of the secretory and endocytic pathways--the endoplasmic reticulum (ER) and endosomes, respectively--are connected through contact sites whose numbers increase as endosomes mature. One function of such sites is to enable dephosphorylation of the cytosolic tails of endosomal signalling receptors by an ER-associated phosphatase, whereas others serve to negatively control the association of endosomes with the minus-end-directed microtubule motor dynein or mediate endosome fission. Cholesterol transfer and Ca(2+) exchange have been proposed as additional functions of such sites. However, the compositions, activities and regulations of ER-endosome contact sites remain incompletely understood. Here we show in human and rat cell lines that protrudin, an ER protein that promotes protrusion and neurite outgrowth, forms contact sites with late endosomes (LEs) via coincident detection of the small GTPase RAB7 and phosphatidylinositol 3-phosphate (PtdIns(3)P). These contact sites mediate transfer of the microtubule motor kinesin 1 from protrudin to the motor adaptor FYCO1 on LEs. Repeated LE-ER contacts promote microtubule-dependent translocation of LEs to the cell periphery and subsequent synaptotagmin-VII-dependent fusion with the plasma membrane. Such fusion induces outgrowth of protrusions and neurites, which requires the abilities of protrudin and FYCO1 to interact with LEs and kinesin 1. Thus, protrudin-containing ER-LE contact sites are platforms for kinesin-1 loading onto LEs, and kinesin-1-mediated translocation of LEs to the plasma membrane, fuelled by repeated ER contacts, promotes protrusion and neurite outgrowth.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Raiborg, Camilla -- Wenzel, Eva M -- Pedersen, Nina M -- Olsvik, Hallvard -- Schink, Kay O -- Schultz, Sebastian W -- Vietri, Marina -- Nisi, Veronica -- Bucci, Cecilia -- Brech, Andreas -- Johansen, Terje -- Stenmark, Harald -- England -- Nature. 2015 Apr 9;520(7546):234-8. doi: 10.1038/nature14359.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway [2] Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway. ; Institute of Medical Biology, University of Tromso - The Arctic University of Norway, N-9037 Tromso, Norway. ; Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Monteroni 165, 73100 Lecce, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25855459" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Biological Transport ; Cell Line ; Cell Membrane/metabolism ; DNA-Binding Proteins/metabolism ; Endoplasmic Reticulum/*metabolism ; Endosomes/*metabolism ; HeLa Cells ; Humans ; Kinesin/metabolism ; Microtubules/metabolism ; Neurites/*metabolism ; Phosphatidylinositol Phosphates/metabolism ; Rats ; Synaptotagmins/metabolism ; Transcription Factors/metabolism ; Vesicular Transport Proteins/metabolism ; rab GTP-Binding Proteins/metabolism
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    An atomic structure of human gamma-secretase (2015)
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    Publication Date: 2015-08-19
    Description: Dysfunction of the intramembrane protease gamma-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human gamma-secretase at 3.4 A resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of gamma-secretase function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568306/" 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/PMC4568306/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bai, Xiao-chen -- Yan, Chuangye -- Yang, Guanghui -- Lu, Peilong -- Ma, Dan -- Sun, Linfeng -- Zhou, Rui -- Scheres, Sjors H W -- Shi, Yigong -- MC_UP_A025_101/Medical Research Council/United Kingdom -- MC_UP_A025_1013/Medical Research Council/United Kingdom -- England -- Nature. 2015 Sep 10;525(7568):212-7. doi: 10.1038/nature14892. Epub 2015 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. ; Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26280335" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/genetics ; Amyloid Precursor Protein ; Secretases/*chemistry/genetics/metabolism/*ultrastructure ; Binding Sites ; *Cryoelectron Microscopy ; Humans ; Membrane Glycoproteins/*chemistry/metabolism/*ultrastructure ; Models, Molecular ; Mutation ; Presenilin-1/*chemistry/genetics/*ultrastructure ; Protein Structure, Tertiary ; Protein Subunits/chemistry/genetics/metabolism
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    Propagation of conformational changes during mu-opioid receptor activation (2015)
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    Publication Date: 2015-08-08
    Description: micro-Opioid receptors (microORs) are G-protein-coupled receptors that are activated by a structurally diverse spectrum of natural and synthetic agonists including endogenous endorphin peptides, morphine and methadone. The recent structures of the muOR in inactive and agonist-induced active states (Huang et al., ref. 2) provide snapshots of the receptor at the beginning and end of a signalling event, but little is known about the dynamic sequence of events that span these two states. Here we use solution-state NMR to examine the process of muOR activation using a purified receptor (mouse sequence) preparation in an amphiphile membrane-like environment. We obtain spectra of the muOR in the absence of ligand, and in the presence of the high-affinity agonist BU72 alone, or with BU72 and a G protein mimetic nanobody. Our results show that conformational changes in transmembrane segments 5 and 6 (TM5 and TM6), which are required for the full engagement of a G protein, are almost completely dependent on the presence of both the agonist and the G protein mimetic nanobody, revealing a weak allosteric coupling between the agonist-binding pocket and the G-protein-coupling interface (TM5 and TM6), similar to that observed for the beta2-adrenergic receptor. Unexpectedly, in the presence of agonist alone, we find larger spectral changes involving intracellular loop 1 and helix 8 compared to changes in TM5 and TM6. These results suggest that one or both of these domains may play a role in the initial interaction with the G protein, and that TM5 and TM6 are only engaged later in the process of complex formation. The initial interactions between the G protein and intracellular loop 1 and/or helix 8 may be involved in G-protein coupling specificity, as has been suggested for other family A G-protein-coupled receptors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sounier, Remy -- Mas, Camille -- Steyaert, Jan -- Laeremans, Toon -- Manglik, Aashish -- Huang, Weijiao -- Kobilka, Brian K -- Demene, Helene -- Granier, Sebastien -- DA036246/DA/NIDA NIH HHS/ -- R37 DA036246/DA/NIDA NIH HHS/ -- T32 GM008294/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Aug 20;524(7565):375-8. doi: 10.1038/nature14680. Epub 2015 Aug 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut de Genomique Fonctionnelle, CNRS UMR-5203 INSERM U1191, University of Montpellier, F-34000 Montpellier, France. ; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium. ; Structural Biology Research Center, VIB, Pleinlaan 2, B-1050 Brussels, Belgium. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA. ; Centre de Biochimie Structurale, CNRS UMR 5048-INSERM 1054- University of Montpellier, 29 rue de Navacelles, 34090 Montpellier Cedex, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26245377" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Animals ; Binding Sites ; Heterotrimeric GTP-Binding Proteins/metabolism ; Lysine/metabolism ; Mice ; Models, Molecular ; Morphinans/chemistry/metabolism/pharmacology ; Nuclear Magnetic Resonance, Biomolecular ; Protein Binding ; Protein Conformation/drug effects ; Pyrroles/chemistry/metabolism/pharmacology ; Receptors, Adrenergic, beta-2/chemistry ; Receptors, Opioid, mu/*chemistry/*metabolism ; Single-Chain Antibodies/chemistry/metabolism/pharmacology ; Structure-Activity Relationship ; Substrate Specificity
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    X-ray structure of a mammalian stearoyl-CoA desaturase (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-06-23
    Description: Stearoyl-CoA desaturase (SCD) is conserved in all eukaryotes and introduces the first double bond into saturated fatty acyl-CoAs. Because the monounsaturated products of SCD are key precursors of membrane phospholipids, cholesterol esters and triglycerides, SCD is pivotal in fatty acid metabolism. Humans have two SCD homologues (SCD1 and SCD5), while mice have four (SCD1-SCD4). SCD1-deficient mice do not become obese or diabetic when fed a high-fat diet because of improved lipid metabolic profiles and insulin sensitivity. Thus, SCD1 is a pharmacological target in the treatment of obesity, diabetes and other metabolic diseases. SCD1 is an integral membrane protein located in the endoplasmic reticulum, and catalyses the formation of a cis-double bond between the ninth and tenth carbons of stearoyl- or palmitoyl-CoA. The reaction requires molecular oxygen, which is activated by a di-iron centre, and cytochrome b5, which regenerates the di-iron centre. To understand better the structural basis of these characteristics of SCD function, here we crystallize and solve the structure of mouse SCD1 bound to stearoyl-CoA at 2.6 A resolution. The structure shows a novel fold comprising four transmembrane helices capped by a cytosolic domain, and a plausible pathway for lateral substrate access and product egress. The acyl chain of the bound stearoyl-CoA is enclosed in a tunnel buried in the cytosolic domain, and the geometry of the tunnel and the conformation of the bound acyl chain provide a structural basis for the regioselectivity and stereospecificity of the desaturation reaction. The dimetal centre is coordinated by a unique spacial arrangement of nine conserved histidine residues that implies a potentially novel mechanism for oxygen activation. The structure also illustrates a possible route for electron transfer from cytochrome b5 to the di-iron centre.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689147/" 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/PMC4689147/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bai, Yonghong -- McCoy, Jason G -- Levin, Elena J -- Sobrado, Pablo -- Rajashankar, Kanagalaghatta R -- Fox, Brian G -- Zhou, Ming -- P41 GM103403/GM/NIGMS NIH HHS/ -- P41GM103403/GM/NIGMS NIH HHS/ -- R01 DK088057/DK/NIDDK NIH HHS/ -- R01 GM098878/GM/NIGMS NIH HHS/ -- R01 HL086392/HL/NHLBI NIH HHS/ -- R01DK088057/DK/NIDDK NIH HHS/ -- R01GM050853/GM/NIGMS NIH HHS/ -- R01GM098878/GM/NIGMS NIH HHS/ -- R01HL086392/HL/NHLBI NIH HHS/ -- U54 GM094584/GM/NIGMS NIH HHS/ -- U54GM094584/GM/NIGMS NIH HHS/ -- U54GM095315/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Aug 13;524(7564):252-6. doi: 10.1038/nature14549. Epub 2015 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA. ; NE-CAT and Department of Chemistry and Chemical Biology, Cornell University, Argonne National Laboratory, Argonne, Illinois 60439, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26098370" target="_blank"〉PubMed〈/a〉
    Keywords: Acyl Coenzyme A/chemistry/metabolism ; Animals ; Binding Sites ; Crystallography, X-Ray ; Cytochromes b5/chemistry/metabolism ; Electron Transport ; Histidine/chemistry/metabolism ; Iron/metabolism ; Mice ; Models, Molecular ; Oxygen/metabolism ; Protein Structure, Tertiary ; Static Electricity ; Stearoyl-CoA Desaturase/*chemistry/metabolism ; Structure-Activity Relationship
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    Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation (2015)
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    Publication Date: 2015-12-10
    Description: Inactivation of the TNFAIP3 gene, encoding the A20 protein, is associated with critical inflammatory diseases including multiple sclerosis, rheumatoid arthritis and Crohn's disease. However, the role of A20 in attenuating inflammatory signalling is unclear owing to paradoxical in vitro and in vivo findings. Here we utilize genetically engineered mice bearing mutations in the A20 ovarian tumour (OTU)-type deubiquitinase domain or in the zinc finger-4 (ZnF4) ubiquitin-binding motif to investigate these discrepancies. We find that phosphorylation of A20 promotes cleavage of Lys63-linked polyubiquitin chains by the OTU domain and enhances ZnF4-mediated substrate ubiquitination. Additionally, levels of linear ubiquitination dictate whether A20-deficient cells die in response to tumour necrosis factor. Mechanistically, linear ubiquitin chains preserve the architecture of the TNFR1 signalling complex by blocking A20-mediated disassembly of Lys63-linked polyubiquitin scaffolds. Collectively, our studies reveal molecular mechanisms whereby A20 deubiquitinase activity and ubiquitin binding, linear ubiquitination, and cellular kinases cooperate to regulate inflammation and cell death.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wertz, Ingrid E -- Newton, Kim -- Seshasayee, Dhaya -- Kusam, Saritha -- Lam, Cynthia -- Zhang, Juan -- Popovych, Nataliya -- Helgason, Elizabeth -- Schoeffler, Allyn -- Jeet, Surinder -- Ramamoorthi, Nandhini -- Kategaya, Lorna -- Newman, Robert J -- Horikawa, Keisuke -- Dugger, Debra -- Sandoval, Wendy -- Mukund, Susmith -- Zindal, Anuradha -- Martin, Flavius -- Quan, Clifford -- Tom, Jeffrey -- Fairbrother, Wayne J -- Townsend, Michael -- Warming, Soren -- DeVoss, Jason -- Liu, Jinfeng -- Dueber, Erin -- Caplazi, Patrick -- Lee, Wyne P -- Goodnow, Christopher C -- Balazs, Mercedesz -- Yu, Kebing -- Kolumam, Ganesh -- Dixit, Vishva M -- England -- Nature. 2015 Dec 17;528(7582):370-5. doi: 10.1038/nature16165. Epub 2015 Dec 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Discovery Oncology, Genentech, South San Francisco, California 94080, USA. ; Early Discovery Biochemistry, Genentech, South San Francisco, California 94080, USA. ; Physiological Chemistry, Genentech, South San Francisco, California 94080, USA. ; Immunology, Genentech, South San Francisco, California 94080, USA. ; Molecular Biology, Genentech, South San Francisco, California 94080, USA. ; Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia. ; Protein Chemistry, Genentech, South San Francisco, California 94080, USA. ; Structural Biology, Genentech, South San Francisco, California 94080, USA. ; Bioinformatics, Genentech, South San Francisco, California 94080, USA. ; Pathology, Genentech, South San Francisco, California 94080, USA. ; Immunogenomics Laboratory, Immunology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Sydney, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26649818" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Death ; Cysteine Endopeptidases/chemistry/genetics/*metabolism ; Female ; Inflammation/genetics/*metabolism/pathology ; Intracellular Signaling Peptides and Proteins/chemistry/genetics/*metabolism ; Lysine/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mutation ; Phosphorylation ; Polyubiquitin/chemistry/metabolism ; Protein Binding ; Protein Kinases/metabolism ; Signal Transduction ; Tumor Necrosis Factor-alpha/metabolism ; Ubiquitin/*chemistry/*metabolism ; Ubiquitination
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    Cryo-electron microscopy structure of the Slo2.2 Na(+)-activated K(+) channel (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-10-06
    Description: Na(+)-activated K(+) channels are members of the Slo family of large conductance K(+) channels that are widely expressed in the brain, where their opening regulates neuronal excitability. These channels fulfil a number of biological roles and have intriguing biophysical properties, including conductance levels that are ten times those of most other K(+) channels and gating sensitivity to intracellular Na(+). Here we present the structure of a complete Na(+)-activated K(+) channel, chicken Slo2.2, in the Na(+)-free state, determined by cryo-electron microscopy at a nominal resolution of 4.5 angstroms. The channel is composed of a large cytoplasmic gating ring, in which resides the Na(+)-binding site and a transmembrane domain that closely resembles voltage-gated K(+) channels. In the structure, the cytoplasmic domain adopts a closed conformation and the ion conduction pore is also closed. The structure reveals features that can explain the unusually high conductance of Slo channels and how contraction of the cytoplasmic gating ring closes the pore.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hite, Richard K -- Yuan, Peng -- Li, Zongli -- Hsuing, Yichun -- Walz, Thomas -- MacKinnon, Roderick -- GM43949/GM/NIGMS NIH HHS/ -- R01 GM043949/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Nov 12;527(7577):198-203. doi: 10.1038/nature14958. Epub 2015 Oct 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Rockefeller University and Howard Hughes Medical Institute, 1230 York Avenue, New York, New York 10065, USA. ; Department of Cell Biology and Howard Hughes Medical Institute, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26436452" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; *Chickens ; *Cryoelectron Microscopy ; Cytoplasm/metabolism ; Electric Conductivity ; Ion Channel Gating ; Ion Transport ; Models, Molecular ; Potassium Channels/chemistry/metabolism/*ultrastructure ; Protein Structure, Tertiary ; Sodium/metabolism ; Structure-Activity Relationship
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    Tumour exosome integrins determine organotropic metastasis (2015)
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    Publication Date: 2015-11-03
    Description: Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins alpha6beta4 and alpha6beta1 were associated with lung metastasis, while exosomal integrin alphavbeta5 was linked to liver metastasis. Targeting the integrins alpha6beta4 and alphavbeta5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hoshino, Ayuko -- Costa-Silva, Bruno -- Shen, Tang-Long -- Rodrigues, Goncalo -- Hashimoto, Ayako -- Tesic Mark, Milica -- Molina, Henrik -- Kohsaka, Shinji -- Di Giannatale, Angela -- Ceder, Sophia -- Singh, Swarnima -- Williams, Caitlin -- Soplop, Nadine -- Uryu, Kunihiro -- Pharmer, Lindsay -- King, Tari -- Bojmar, Linda -- Davies, Alexander E -- Ararso, Yonathan -- Zhang, Tuo -- Zhang, Haiying -- Hernandez, Jonathan -- Weiss, Joshua M -- Dumont-Cole, Vanessa D -- Kramer, Kimberly -- Wexler, Leonard H -- Narendran, Aru -- Schwartz, Gary K -- Healey, John H -- Sandstrom, Per -- Labori, Knut Jorgen -- Kure, Elin H -- Grandgenett, Paul M -- Hollingsworth, Michael A -- de Sousa, Maria -- Kaur, Sukhwinder -- Jain, Maneesh -- Mallya, Kavita -- Batra, Surinder K -- Jarnagin, William R -- Brady, Mary S -- Fodstad, Oystein -- Muller, Volkmar -- Pantel, Klaus -- Minn, Andy J -- Bissell, Mina J -- Garcia, Benjamin A -- Kang, Yibin -- Rajasekhar, Vinagolu K -- Ghajar, Cyrus M -- Matei, Irina -- Peinado, Hector -- Bromberg, Jacqueline -- Lyden, David -- R01 CA169416/CA/NCI NIH HHS/ -- R01-CA169416/CA/NCI NIH HHS/ -- U01 CA169538/CA/NCI NIH HHS/ -- U01-CA169538/CA/NCI NIH HHS/ -- England -- Nature. 2015 Nov 19;527(7578):329-35. doi: 10.1038/nature15756. Epub 2015 Oct 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10021, USA. ; Department of Plant Pathology and Microbiology and Center for Biotechnology, National Taiwan University, Taipei 10617, Taiwan. ; Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, 4099-003 Porto, Portugal. ; Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan. ; Proteomics Resource Center, The Rockefeller University, New York, New York 10065, USA. ; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Oncology and Pathology, Karolinska Institutet, 17176 Stockholm, Sweden. ; Electron Microscopy Resource Center (EMRC), Rockefeller University, New York, New York 10065, USA. ; Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA. ; Department of Surgery, County Council of Ostergotland, and Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, 58185 Linkoping, Sweden. ; Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. ; Genomics Resources Core Facility, Weill Cornell Medicine, New York, New York 10021, USA. ; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta T3B 6A8, Canada. ; Division of Hematology/Oncology, Columbia University School of Medicine, New York, New York 10032, USA. ; Orthopaedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Nydalen, Oslo 0424, Norway. ; Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Nydalen, Oslo 0424, Norway. ; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA. ; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA. ; Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Nydalen, Oslo 0424, Norway. ; Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Blindern, Oslo 0318, Norway. ; Department of Gynecology, University Medical Center, Martinistrasse 52, 20246 Hamburg, Germany. ; Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. ; Department of Radiation Oncology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA. ; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA. ; Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; Microenvironment and Metastasis Laboratory, Department of Molecular Oncology, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Medicine, Weill Cornell Medicine, New York, New York 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26524530" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomarkers/metabolism ; Brain/cytology/*metabolism ; Cell Line, Tumor ; Endothelial Cells/cytology/metabolism ; Epithelial Cells/cytology/metabolism ; Exosomes/*metabolism ; Female ; Fibroblasts/cytology/metabolism ; Genes, src ; Humans ; Integrin alpha6beta1/metabolism ; Integrin alpha6beta4/antagonists & inhibitors/metabolism ; Integrin beta Chains/metabolism ; Integrin beta4/metabolism ; Integrins/antagonists & inhibitors/*metabolism ; Kupffer Cells/cytology/metabolism ; Liver/cytology/*metabolism ; Lung/cytology/*metabolism ; Mice ; Mice, Inbred C57BL ; Neoplasm Metastasis/*pathology/*prevention & control ; Organ Specificity ; Phosphorylation ; Receptors, Vitronectin/antagonists & inhibitors/metabolism ; S100 Proteins/genetics ; *Tropism
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    Microbiology: Taking the bad with the good (2015)
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    Publication Date: 2015-05-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bergstrom, Carl T -- Kerr, Benjamin -- England -- Nature. 2015 May 28;521(7553):431-2.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25992542" target="_blank"〉PubMed〈/a〉
    Keywords: Anti-Bacterial Agents/*biosynthesis/*metabolism ; *Ecosystem ; *Models, Biological ; *Soil Microbiology
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    Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis (2015)
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    Publication Date: 2015-11-13
    Description: Cancer cells hijack and remodel existing metabolic pathways for their benefit. Argininosuccinate synthase (ASS1) is a urea cycle enzyme that is essential in the conversion of nitrogen from ammonia and aspartate to urea. A decrease in nitrogen flux through ASS1 in the liver causes the urea cycle disorder citrullinaemia. In contrast to the well-studied consequences of loss of ASS1 activity on ureagenesis, the purpose of its somatic silencing in multiple cancers is largely unknown. Here we show that decreased activity of ASS1 in cancers supports proliferation by facilitating pyrimidine synthesis via CAD (carbamoyl-phosphate synthase 2, aspartate transcarbamylase, and dihydroorotase complex) activation. Our studies were initiated by delineating the consequences of loss of ASS1 activity in humans with two types of citrullinaemia. We find that in citrullinaemia type I (CTLN I), which is caused by deficiency of ASS1, there is increased pyrimidine synthesis and proliferation compared with citrullinaemia type II (CTLN II), in which there is decreased substrate availability for ASS1 caused by deficiency of the aspartate transporter citrin. Building on these results, we demonstrate that ASS1 deficiency in cancer increases cytosolic aspartate levels, which increases CAD activation by upregulating its substrate availability and by increasing its phosphorylation by S6K1 through the mammalian target of rapamycin (mTOR) pathway. Decreasing CAD activity by blocking citrin, the mTOR signalling, or pyrimidine synthesis decreases proliferation and thus may serve as a therapeutic strategy in multiple cancers where ASS1 is downregulated. Our results demonstrate that ASS1 downregulation is a novel mechanism supporting cancerous proliferation, and they provide a metabolic link between the urea cycle enzymes and pyrimidine synthesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655447/" 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/PMC4655447/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rabinovich, Shiran -- Adler, Lital -- Yizhak, Keren -- Sarver, Alona -- Silberman, Alon -- Agron, Shani -- Stettner, Noa -- Sun, Qin -- Brandis, Alexander -- Helbling, Daniel -- Korman, Stanley -- Itzkovitz, Shalev -- Dimmock, David -- Ulitsky, Igor -- Nagamani, Sandesh C S -- Ruppin, Eytan -- Erez, Ayelet -- 1 U54 HD083092/HD/NICHD NIH HHS/ -- England -- Nature. 2015 Nov 19;527(7578):379-83. doi: 10.1038/nature15529. Epub 2015 Nov 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel. ; The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel. ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. ; Biological Services, Weizmann Institute of Science, Rehovot 69978, Israel. ; Human and Molecular Genetic and Biochemistry Center, Medical College Wisconsin, Milwaukee, Wisconsin 53226, USA. ; Genetic and Metabolic Center, Hadassah Medical Center, Jerusalem 91120, Israel. ; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 69978, Israel. ; Texas Children's Hospital, Houston, Texas 77030, USA. ; The Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. ; Center for Bioinformatics and Computational Biology &Department of Computer Science, University of Maryland, College Park, Maryland 20742, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26560030" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argininosuccinate Synthase/*deficiency/metabolism ; Aspartate Carbamoyltransferase/metabolism ; Aspartic Acid/*metabolism ; Calcium-Binding Proteins/antagonists & inhibitors/metabolism ; Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Citrullinemia/metabolism ; Cytosol/metabolism ; Dihydroorotase/metabolism ; Down-Regulation ; Enzyme Activation ; Humans ; Male ; Mice ; Mice, SCID ; Neoplasms/enzymology/*metabolism/pathology ; Organic Anion Transporters/antagonists & inhibitors/metabolism ; Phosphorylation ; Pyrimidines/*biosynthesis ; TOR Serine-Threonine Kinases/metabolism
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    Environment: Polluters migrate to China's poor areas (2015)
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    Details
    Publication Date: 2015-02-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miao, Xin -- Tang, Yanhong -- Wong, Christina W Y -- England -- Nature. 2015 Feb 26;518(7540):483. doi: 10.1038/518483d.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Harbin Institute of Technology, Harbin, China. ; Northeast Agricultural University, Harbin, China. ; The Hong Kong Polytechnic University, Kowloon, Hong Kong.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25719657" target="_blank"〉PubMed〈/a〉
    Keywords: China ; *Ecosystem ; Environmental Policy/economics/*legislation & jurisprudence ; Environmental Pollution/*analysis/economics/*legislation & ; jurisprudence/prevention & control ; Human Migration ; Industrial Waste/analysis/economics/legislation & jurisprudence ; Industry/*legislation & jurisprudence/trends ; *Poverty
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Crystal structure of the RNA-dependent RNA polymerase from influenza C virus (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-10-28
    Description: Negative-sense RNA viruses, such as influenza, encode large, multidomain RNA-dependent RNA polymerases that can both transcribe and replicate the viral RNA genome. In influenza virus, the polymerase (FluPol) is composed of three polypeptides: PB1, PB2 and PA/P3. PB1 houses the polymerase active site, whereas PB2 and PA/P3 contain, respectively, cap-binding and endonuclease domains required for transcription initiation by cap-snatching. Replication occurs through de novo initiation and involves a complementary RNA intermediate. Currently available structures of the influenza A and B virus polymerases include promoter RNA (the 5' and 3' termini of viral genome segments), showing FluPol in transcription pre-initiation states. Here we report the structure of apo-FluPol from an influenza C virus, solved by X-ray crystallography to 3.9 A, revealing a new 'closed' conformation. The apo-FluPol forms a compact particle with PB1 at its centre, capped on one face by PB2 and clamped between the two globular domains of P3. Notably, this structure is radically different from those of promoter-bound FluPols. The endonuclease domain of P3 and the domains within the carboxy-terminal two-thirds of PB2 are completely rearranged. The cap-binding site is occluded by PB2, resulting in a conformation that is incompatible with transcription initiation. Thus, our structure captures FluPol in a closed, transcription pre-activation state. This reveals the conformation of newly made apo-FluPol in an infected cell, but may also apply to FluPol in the context of a non-transcribing ribonucleoprotein complex. Comparison of the apo-FluPol structure with those of promoter-bound FluPols allows us to propose a mechanism for FluPol activation. Our study demonstrates the remarkable flexibility of influenza virus RNA polymerase, and aids our understanding of the mechanisms controlling transcription and genome replication.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hengrung, Narin -- El Omari, Kamel -- Serna Martin, Itziar -- Vreede, Frank T -- Cusack, Stephen -- Rambo, Robert P -- Vonrhein, Clemens -- Bricogne, Gerard -- Stuart, David I -- Grimes, Jonathan M -- Fodor, Ervin -- 075491/Z/04/Wellcome Trust/United Kingdom -- 092931/Z/10/Z/Wellcome Trust/United Kingdom -- G1000099/Medical Research Council/United Kingdom -- G1100138/Medical Research Council/United Kingdom -- MR/K000241/1/Medical Research Council/United Kingdom -- England -- Nature. 2015 Nov 5;527(7576):114-7. doi: 10.1038/nature15525. Epub 2015 Oct 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK. ; Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, University of Oxford, Oxford OX3 7BN, UK. ; European Molecular Biology Laboratory, Grenoble Outstation and University Grenoble Alpes-Centre National de la Recherche Scientifique-EMBL Unit of Virus Host-Cell Interactions, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble Cedex 9, France. ; Diamond Light Source Ltd, Harwell Science &Innovation Campus, Didcot OX11 0DE, UK. ; Global Phasing Ltd, Sheraton House, Castle Park, Cambridge CB3 0AX, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26503046" target="_blank"〉PubMed〈/a〉
    Keywords: Apoenzymes/chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Endonucleases/chemistry/metabolism ; Enzyme Activation ; Influenzavirus C/*enzymology ; Models, Molecular ; Peptide Chain Initiation, Translational ; Promoter Regions, Genetic/genetics ; Protein Binding ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; RNA Caps/metabolism ; RNA Replicase/*chemistry/metabolism ; RNA, Viral/biosynthesis/metabolism ; Ribonucleoproteins/chemistry
    Print ISSN: 0028-0836
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    Structural imprints in vivo decode RNA regulatory mechanisms (2015)
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    Publication Date: 2015-03-25
    Description: Visualizing the physical basis for molecular behaviour inside living cells is a great challenge for biology. RNAs are central to biological regulation, and the ability of RNA to adopt specific structures intimately controls every step of the gene expression program. However, our understanding of physiological RNA structures is limited; current in vivo RNA structure profiles include only two of the four nucleotides that make up RNA. Here we present a novel biochemical approach, in vivo click selective 2'-hydroxyl acylation and profiling experiment (icSHAPE), which enables the first global view, to our knowledge, of RNA secondary structures in living cells for all four bases. icSHAPE of the mouse embryonic stem cell transcriptome versus purified RNA folded in vitro shows that the structural dynamics of RNA in the cellular environment distinguish different classes of RNAs and regulatory elements. Structural signatures at translational start sites and ribosome pause sites are conserved from in vitro conditions, suggesting that these RNA elements are programmed by sequence. In contrast, focal structural rearrangements in vivo reveal precise interfaces of RNA with RNA-binding proteins or RNA-modification sites that are consistent with atomic-resolution structural data. Such dynamic structural footprints enable accurate prediction of RNA-protein interactions and N(6)-methyladenosine (m(6)A) modification genome wide. These results open the door for structural genomics of RNA in living cells and reveal key physiological structures controlling gene expression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376618/" 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/PMC4376618/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Spitale, Robert C -- Flynn, Ryan A -- Zhang, Qiangfeng Cliff -- Crisalli, Pete -- Lee, Byron -- Jung, Jong-Wha -- Kuchelmeister, Hannes Y -- Batista, Pedro J -- Torre, Eduardo A -- Kool, Eric T -- Chang, Howard Y -- F30 CA189514/CA/NCI NIH HHS/ -- F30CA189514/CA/NCI NIH HHS/ -- P50 HG007735/HG/NHGRI NIH HHS/ -- P50HG007735/HG/NHGRI NIH HHS/ -- R01 HG004361/HG/NHGRI NIH HHS/ -- R01HG004361/HG/NHGRI NIH HHS/ -- T32 CA009302/CA/NCI NIH HHS/ -- T32AR007422/AR/NIAMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Mar 26;519(7544):486-90. doi: 10.1038/nature14263. Epub 2015 Mar 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA. ; Department of Chemistry, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25799993" target="_blank"〉PubMed〈/a〉
    Keywords: Acylation ; Adenosine/analogs & derivatives ; Animals ; Binding Sites ; Cell Survival ; Click Chemistry ; Computational Biology ; Embryonic Stem Cells/cytology/metabolism ; *Gene Expression Regulation/genetics ; Genome/genetics ; Mice ; Models, Molecular ; *Nucleic Acid Conformation ; Protein Biosynthesis/genetics ; RNA/*chemistry/classification/*genetics/metabolism ; RNA-Binding Proteins/metabolism ; Regulatory Sequences, Ribonucleic Acid/genetics ; Ribosomes/metabolism ; Transcriptome/genetics
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    Conformational control of DNA target cleavage by CRISPR-Cas9 (2015)
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    Publication Date: 2015-11-03
    Description: Cas9 is an RNA-guided DNA endonuclease that targets foreign DNA for destruction as part of a bacterial adaptive immune system mediated by clustered regularly interspaced short palindromic repeats (CRISPR). Together with single-guide RNAs, Cas9 also functions as a powerful genome engineering tool in plants and animals, and efforts are underway to increase the efficiency and specificity of DNA targeting for potential therapeutic applications. Studies of off-target effects have shown that DNA binding is far more promiscuous than DNA cleavage, yet the molecular cues that govern strand scission have not been elucidated. Here we show that the conformational state of the HNH nuclease domain directly controls DNA cleavage activity. Using intramolecular Forster resonance energy transfer experiments to detect relative orientations of the Cas9 catalytic domains when associated with on- and off-target DNA, we find that DNA cleavage efficiencies scale with the extent to which the HNH domain samples an activated conformation. We furthermore uncover a surprising mode of allosteric communication that ensures concerted firing of both Cas9 nuclease domains. Our results highlight a proofreading mechanism beyond initial protospacer adjacent motif (PAM) recognition and RNA-DNA base-pairing that serves as a final specificity checkpoint before DNA double-strand break formation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sternberg, Samuel H -- LaFrance, Benjamin -- Kaplan, Matias -- Doudna, Jennifer A -- T32GM007232/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Nov 5;527(7576):110-3. doi: 10.1038/nature15544. Epub 2015 Oct 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of California, Berkeley, California 94720, USA. ; Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA. ; Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA. ; Innovative Genomics Initiative, University of California, Berkeley, California 94720, USA. ; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26524520" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Bacterial Proteins/chemistry/metabolism ; Base Pairing ; Binding Sites ; CRISPR-Associated Proteins/*chemistry/*metabolism ; *CRISPR-Cas Systems ; Catalytic Domain ; DNA/chemistry/*metabolism ; DNA Breaks, Double-Stranded ; *DNA Cleavage ; Endonucleases/chemistry/*metabolism ; Fluorescence Resonance Energy Transfer ; *Genetic Engineering ; Models, Molecular ; RNA, Guide/chemistry/metabolism ; Streptococcus pyogenes
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Structural insights into micro-opioid receptor activation (2015)
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    Publication Date: 2015-08-08
    Description: Activation of the mu-opioid receptor (muOR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for muOR activation, here we report a 2.1 A X-ray crystal structure of the murine muOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the muOR binding pocket are subtle and differ from those observed for agonist-bound structures of the beta2-adrenergic receptor (beta2AR) and the M2 muscarinic receptor. Comparison with active beta2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the muOR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three G-protein-coupled receptors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639397/" 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/PMC4639397/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Weijiao -- Manglik, Aashish -- Venkatakrishnan, A J -- Laeremans, Toon -- Feinberg, Evan N -- Sanborn, Adrian L -- Kato, Hideaki E -- Livingston, Kathryn E -- Thorsen, Thor S -- Kling, Ralf C -- Granier, Sebastien -- Gmeiner, Peter -- Husbands, Stephen M -- Traynor, John R -- Weis, William I -- Steyaert, Jan -- Dror, Ron O -- Kobilka, Brian K -- R01GM083118/GM/NIGMS NIH HHS/ -- R37 DA036246/DA/NIDA NIH HHS/ -- R37DA036246/DA/NIDA NIH HHS/ -- T32 GM008294/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Aug 20;524(7565):315-21. doi: 10.1038/nature14886. Epub 2015 Aug 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA. ; Department of Computer Science, Stanford University, 318 Campus Drive, Stanford, California 94305, USA. ; Institute for Computational and Mathematical Engineering, Stanford University, 475 Via Ortega, Stanford, California 94305, USA. ; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium. ; Structural Biology Research Center, VIB, Pleinlaan 2, B-1050 Brussels, Belgium. ; Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Chemistry and Pharmacy, Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany. ; Institut de Genomique Fonctionnelle, CNRS UMR-5203 INSERM U1191, University of Montpellier, F-34000 Montpellier, France. ; Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK. ; Department of Structural Biology, Stanford University School of Medicine, 299 Campus Drive, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26245379" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Animals ; Binding Sites ; Crystallography, X-Ray ; Heterotrimeric GTP-Binding Proteins/chemistry/metabolism ; Mice ; Models, Molecular ; Molecular Dynamics Simulation ; Morphinans/chemistry/metabolism/pharmacology ; Protein Stability/drug effects ; Protein Structure, Tertiary ; Pyrroles/chemistry/metabolism/pharmacology ; Receptor, Muscarinic M2/chemistry ; Receptors, Adrenergic, beta-2/chemistry ; Receptors, Opioid, mu/agonists/*chemistry/*metabolism ; Single-Chain Antibodies/chemistry/pharmacology ; Structure-Activity Relationship
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    Competitive binding of antagonistic peptides fine-tunes stomatal patterning (2015)
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    Publication Date: 2015-06-18
    Description: During development, cells interpret complex and often conflicting signals to make optimal decisions. Plant stomata, the cellular interface between a plant and the atmosphere, develop according to positional cues, which include a family of secreted peptides called epidermal patterning factors (EPFs). How these signalling peptides orchestrate pattern formation at a molecular level remains unclear. Here we report in Arabidopsis that Stomagen (also called EPF-LIKE9) peptide, which promotes stomatal development, requires ERECTA (ER)-family receptor kinases and interferes with the inhibition of stomatal development by the EPIDERMAL PATTERNING FACTOR 2 (EPF2)-ER module. Both EPF2 and Stomagen directly bind to ER and its co-receptor TOO MANY MOUTHS. Stomagen peptide competitively replaced EPF2 binding to ER. Furthermore, application of EPF2, but not Stomagen, elicited rapid phosphorylation of downstream signalling components in vivo. Our findings demonstrate how a plant receptor agonist and antagonist define inhibitory and inductive cues to fine-tune tissue patterning on the plant epidermis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532310/" 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/PMC4532310/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Jin Suk -- Hnilova, Marketa -- Maes, Michal -- Lin, Ya-Chen Lisa -- Putarjunan, Aarthi -- Han, Soon-Ki -- Avila, Julian -- Torii, Keiko U -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jun 25;522(7557):439-43. doi: 10.1038/nature14561. Epub 2015 Jun 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA [2] Department of Biology, University of Washington, Seattle, Washington 98195, USA. ; Department of Materials Science and Engineering, University of Washington, Seattle, Washington 98195, USA. ; Department of Biology, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26083750" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/genetics/growth & development/*metabolism ; Arabidopsis Proteins/genetics/*metabolism ; *Binding, Competitive ; DNA-Binding Proteins/*metabolism ; Enzyme Activation ; Hypocotyl/metabolism ; MAP Kinase Signaling System ; Mitogen-Activated Protein Kinases/metabolism ; Phosphorylation ; Plant Stomata/*growth & development/*metabolism ; Protein-Serine-Threonine Kinases/deficiency/genetics/*metabolism ; Receptors, Cell Surface/deficiency/genetics/*metabolism ; Seedlings/enzymology/metabolism ; Transcription Factors/*metabolism
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    Crystal structures of the human adiponectin receptors (2015)
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    Publication Date: 2015-04-10
    Description: Adiponectin stimulation of its receptors, AdipoR1 and AdipoR2, increases the activities of 5' AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR), respectively, thereby contributing to healthy longevity as key anti-diabetic molecules. AdipoR1 and AdipoR2 were predicted to contain seven transmembrane helices with the opposite topology to G-protein-coupled receptors. Here we report the crystal structures of human AdipoR1 and AdipoR2 at 2.9 and 2.4 A resolution, respectively, which represent a novel class of receptor structure. The seven-transmembrane helices, conformationally distinct from those of G-protein-coupled receptors, enclose a large cavity where three conserved histidine residues coordinate a zinc ion. The zinc-binding structure may have a role in the adiponectin-stimulated AMPK phosphorylation and UCP2 upregulation. Adiponectin may broadly interact with the extracellular face, rather than the carboxy-terminal tail, of the receptors. The present information will facilitate the understanding of novel structure-function relationships and the development and optimization of AdipoR agonists for the treatment of obesity-related diseases, such as type 2 diabetes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477036/" 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/PMC4477036/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tanabe, Hiroaki -- Fujii, Yoshifumi -- Okada-Iwabu, Miki -- Iwabu, Masato -- Nakamura, Yoshihiro -- Hosaka, Toshiaki -- Motoyama, Kanna -- Ikeda, Mariko -- Wakiyama, Motoaki -- Terada, Takaho -- Ohsawa, Noboru -- Hato, Masakatsu -- Ogasawara, Satoshi -- Hino, Tomoya -- Murata, Takeshi -- Iwata, So -- Hirata, Kunio -- Kawano, Yoshiaki -- Yamamoto, Masaki -- Kimura-Someya, Tomomi -- Shirouzu, Mikako -- Yamauchi, Toshimasa -- Kadowaki, Takashi -- Yokoyama, Shigeyuki -- 062164/Z/00/Z/Wellcome Trust/United Kingdom -- 089809/Wellcome Trust/United Kingdom -- BB/G02325/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/G023425/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2015 Apr 16;520(7547):312-6. doi: 10.1038/nature14301. Epub 2015 Apr 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Biophysics and Biochemistry and Laboratory of Structural Biology, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [4] RIKEN Structural Biology Laboratory, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] RIKEN Structural Biology Laboratory, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; 1] Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [2] Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. ; 1] Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [2] Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [3] RIKEN Structural Biology Laboratory, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. ; 1] Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [2] JST, Research Acceleration Program, Membrane Protein Crystallography Project, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [3] JST, Research Acceleration Program, Membrane Protein Crystallography Project, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan [4] Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-cho, Inage, Chiba 263-8522, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [3] JST, Research Acceleration Program, Membrane Protein Crystallography Project, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan [4] Division of Molecular Biosciences, Membrane Protein Crystallography Group, Imperial College, London SW7 2AZ, UK [5] Diamond Light Source, Harwell Science and Innovation Campus, Chilton, Didcot, Oxfordshire OX11 0DE, UK [6] RIKEN SPring-8 Center, Harima Institute, Kouto, Sayo, Hyogo 679-5148, Japan. ; RIKEN SPring-8 Center, Harima Institute, Kouto, Sayo, Hyogo 679-5148, Japan. ; 1] Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [2] Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Biophysics and Biochemistry and Laboratory of Structural Biology, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] RIKEN Structural Biology Laboratory, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25855295" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding Sites ; Crystallography, X-Ray ; Histidine/chemistry/metabolism ; Humans ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; Receptors, Adiponectin/*chemistry/metabolism ; Structure-Activity Relationship ; Zinc/metabolism
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    Atomic structure of the APC/C and its mechanism of protein ubiquitination (2015)
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    Publication Date: 2015-06-18
    Description: The anaphase-promoting complex (APC/C) is a multimeric RING E3 ubiquitin ligase that controls chromosome segregation and mitotic exit. Its regulation by coactivator subunits, phosphorylation, the mitotic checkpoint complex and interphase early mitotic inhibitor 1 (Emi1) ensures the correct order and timing of distinct cell-cycle transitions. Here we use cryo-electron microscopy to determine atomic structures of APC/C-coactivator complexes with either Emi1 or a UbcH10-ubiquitin conjugate. These structures define the architecture of all APC/C subunits, the position of the catalytic module and explain how Emi1 mediates inhibition of the two E2s UbcH10 and Ube2S. Definition of Cdh1 interactions with the APC/C indicates how they are antagonized by Cdh1 phosphorylation. The structure of the APC/C with UbcH10-ubiquitin reveals insights into the initiating ubiquitination reaction. Our results provide a quantitative framework for the design of future experiments to investigate APC/C functions in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608048/" 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/PMC4608048/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chang, Leifu -- Zhang, Ziguo -- Yang, Jing -- McLaughlin, Stephen H -- Barford, David -- A8022/Cancer Research UK/United Kingdom -- MC_UP_1201/6/Medical Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2015 Jun 25;522(7557):450-4. doi: 10.1038/nature14471. Epub 2015 Jun 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26083744" target="_blank"〉PubMed〈/a〉
    Keywords: Anaphase-Promoting Complex-Cyclosome/chemistry/*metabolism/*ultrastructure ; Apc1 Subunit, Anaphase-Promoting ; Complex-Cyclosome/chemistry/metabolism/ultrastructure ; Apc10 Subunit, Anaphase-Promoting ; Complex-Cyclosome/chemistry/metabolism/ultrastructure ; Apc11 Subunit, Anaphase-Promoting Complex-Cyclosome/chemistry/metabolism ; Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome/chemistry/metabolism ; Apc8 Subunit, Anaphase-Promoting ; Complex-Cyclosome/chemistry/metabolism/ultrastructure ; Cadherins/chemistry/metabolism/ultrastructure ; Catalytic Domain ; Cell Cycle Proteins/chemistry/metabolism/ultrastructure ; Cryoelectron Microscopy ; Cytoskeletal Proteins/chemistry/metabolism ; F-Box Proteins/chemistry/metabolism/ultrastructure ; Humans ; Lysine/metabolism ; Models, Molecular ; Phosphorylation ; Protein Binding ; Protein Subunits/chemistry/metabolism ; Structure-Activity Relationship ; Substrate Specificity ; Ubiquitin/chemistry/metabolism/ultrastructure ; Ubiquitin-Conjugating Enzymes/chemistry/metabolism/ultrastructure ; *Ubiquitination
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    Mechanism of phospho-ubiquitin-induced PARKIN activation (2015)
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    Publication Date: 2015-07-15
    Description: The E3 ubiquitin ligase PARKIN (encoded by PARK2) and the protein kinase PINK1 (encoded by PARK6) are mutated in autosomal-recessive juvenile Parkinsonism (AR-JP) and work together in the disposal of damaged mitochondria by mitophagy. PINK1 is stabilized on the outside of depolarized mitochondria and phosphorylates polyubiquitin as well as the PARKIN ubiquitin-like (Ubl) domain. These phosphorylation events lead to PARKIN recruitment to mitochondria, and activation by an unknown allosteric mechanism. Here we present the crystal structure of Pediculus humanus PARKIN in complex with Ser65-phosphorylated ubiquitin (phosphoUb), revealing the molecular basis for PARKIN recruitment and activation. The phosphoUb binding site on PARKIN comprises a conserved phosphate pocket and harbours residues mutated in patients with AR-JP. PhosphoUb binding leads to straightening of a helix in the RING1 domain, and the resulting conformational changes release the Ubl domain from the PARKIN core; this activates PARKIN. Moreover, phosphoUb-mediated Ubl release enhances Ubl phosphorylation by PINK1, leading to conformational changes within the Ubl domain and stabilization of an open, active conformation of PARKIN. We redefine the role of the Ubl domain not only as an inhibitory but also as an activating element that is restrained in inactive PARKIN and released by phosphoUb. Our work opens up new avenues to identify small-molecule PARKIN activators.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wauer, Tobias -- Simicek, Michal -- Schubert, Alexander -- Komander, David -- U105192732/Medical Research Council/United Kingdom -- England -- Nature. 2015 Aug 20;524(7565):370-4. doi: 10.1038/nature14879. Epub 2015 Jul 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26161729" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites/genetics ; Conserved Sequence/genetics ; Crystallography, X-Ray ; Enzyme Activation ; Humans ; Models, Molecular ; Mutation/genetics ; Parkinsonian Disorders/genetics ; Pediculus/*chemistry ; Phosphates/metabolism ; Phosphoproteins/chemistry/metabolism ; Phosphorylation ; Protein Binding ; Protein Kinases/metabolism ; Protein Structure, Tertiary ; Structure-Activity Relationship ; Ubiquitin/*chemistry/*metabolism ; Ubiquitin-Protein Ligases/*chemistry/genetics/*metabolism
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    The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy (2015)
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    Publication Date: 2015-08-13
    Description: Protein aggregates and damaged organelles are tagged with ubiquitin chains to trigger selective autophagy. To initiate mitophagy, the ubiquitin kinase PINK1 phosphorylates ubiquitin to activate the ubiquitin ligase parkin, which builds ubiquitin chains on mitochondrial outer membrane proteins, where they act to recruit autophagy receptors. Using genome editing to knockout five autophagy receptors in HeLa cells, here we show that two receptors previously linked to xenophagy, NDP52 and optineurin, are the primary receptors for PINK1- and parkin-mediated mitophagy. PINK1 recruits NDP52 and optineurin, but not p62, to mitochondria to activate mitophagy directly, independently of parkin. Once recruited to mitochondria, NDP52 and optineurin recruit the autophagy factors ULK1, DFCP1 and WIPI1 to focal spots proximal to mitochondria, revealing a function for these autophagy receptors upstream of LC3. This supports a new model in which PINK1-generated phospho-ubiquitin serves as the autophagy signal on mitochondria, and parkin then acts to amplify this signal. This work also suggests direct and broader roles for ubiquitin phosphorylation in other autophagy pathways.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lazarou, Michael -- Sliter, Danielle A -- Kane, Lesley A -- Sarraf, Shireen A -- Wang, Chunxin -- Burman, Jonathon L -- Sideris, Dionisia P -- Fogel, Adam I -- Youle, Richard J -- Intramural NIH HHS/ -- England -- Nature. 2015 Aug 20;524(7565):309-14. doi: 10.1038/nature14893. Epub 2015 Aug 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26266977" target="_blank"〉PubMed〈/a〉
    Keywords: Autophagy/*physiology ; Carrier Proteins/metabolism ; HeLa Cells ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Membrane Proteins/metabolism ; Microtubule-Associated Proteins/metabolism ; Mitochondria/metabolism ; Mitochondrial Degradation/*physiology ; Mitochondrial Proteins/metabolism ; Models, Biological ; Nuclear Proteins/*metabolism ; Phosphorylation ; Protein Kinases/*metabolism ; Protein-Serine-Threonine Kinases/metabolism ; Signal Transduction ; Transcription Factor TFIIIA/*metabolism ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Intersecting transcription networks constrain gene regulatory evolution (2015)
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    Publication Date: 2015-07-15
    Description: Epistasis-the non-additive interactions between different genetic loci-constrains evolutionary pathways, blocking some and permitting others. For biological networks such as transcription circuits, the nature of these constraints and their consequences are largely unknown. Here we describe the evolutionary pathways of a transcription network that controls the response to mating pheromone in yeast. A component of this network, the transcription regulator Ste12, has evolved two different modes of binding to a set of its target genes. In one group of species, Ste12 binds to specific DNA binding sites, while in another lineage it occupies DNA indirectly, relying on a second transcription regulator to recognize DNA. We show, through the construction of various possible evolutionary intermediates, that evolution of the direct mode of DNA binding was not directly accessible to the ancestor. Instead, it was contingent on a lineage-specific change to an overlapping transcription network with a different function, the specification of cell type. These results show that analysing and predicting the evolution of cis-regulatory regions requires an understanding of their positions in overlapping networks, as this placement constrains the available evolutionary pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531262/" 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/PMC4531262/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sorrells, Trevor R -- Booth, Lauren N -- Tuch, Brian B -- Johnson, Alexander D -- R01 GM037049/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Jul 16;523(7560):361-5. doi: 10.1038/nature14613. Epub 2015 Jul 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry &Biophysics, Department of Microbiology &Immunology, University of California, San Francisco, California 94158, USA [2] Tetrad Graduate Program, University of California, San Francisco, California 94158, USA. ; 1] Department of Biochemistry &Biophysics, Department of Microbiology &Immunology, University of California, San Francisco, California 94158, USA [2] Biological and Medical Informatics Graduate Program, University of California, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26153861" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Binding Sites ; DNA, Fungal/genetics/metabolism ; DNA-Binding Proteins/metabolism ; Enhancer Elements, Genetic/genetics ; Epistasis, Genetic ; *Evolution, Molecular ; Gene Expression Regulation, Fungal/drug effects/*genetics ; Gene Regulatory Networks/drug effects/*genetics ; Genes, Fungal/genetics ; Kluyveromyces/drug effects/genetics/metabolism ; Peptides/metabolism/pharmacology ; Pheromones/metabolism/pharmacology ; Promoter Regions, Genetic/genetics ; Saccharomyces cerevisiae/drug effects/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Transcription Factors/metabolism
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    Lagging-strand replication shapes the mutational landscape of the genome (2015)
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    Publication Date: 2015-01-28
    Description: The origin of mutations is central to understanding evolution and of key relevance to health. Variation occurs non-randomly across the genome, and mechanisms for this remain to be defined. Here we report that the 5' ends of Okazaki fragments have significantly increased levels of nucleotide substitution, indicating a replicative origin for such mutations. Using a novel method, emRiboSeq, we map the genome-wide contribution of polymerases, and show that despite Okazaki fragment processing, DNA synthesized by error-prone polymerase-alpha (Pol-alpha) is retained in vivo, comprising approximately 1.5% of the mature genome. We propose that DNA-binding proteins that rapidly re-associate post-replication act as partial barriers to Pol-delta-mediated displacement of Pol-alpha-synthesized DNA, resulting in incorporation of such Pol-alpha tracts and increased mutation rates at specific sites. We observe a mutational cost to chromatin and regulatory protein binding, resulting in mutation hotspots at regulatory elements, with signatures of this process detectable in both yeast and humans.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374164/" 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/PMC4374164/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reijns, Martin A M -- Kemp, Harriet -- Ding, James -- de Proce, Sophie Marion -- Jackson, Andrew P -- Taylor, Martin S -- MC_PC_U127580972/Medical Research Council/United Kingdom -- MC_PC_U127597124/Medical Research Council/United Kingdom -- MC_U127597124/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2015 Feb 26;518(7540):502-6. doi: 10.1038/nature14183. Epub 2015 Jan 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical and Developmental Genetics, MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. ; Biomedical Systems Analysis, MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25624100" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Chromatin/chemistry/metabolism ; Conserved Sequence/genetics ; DNA/*biosynthesis/*genetics ; DNA Polymerase I/metabolism ; DNA Polymerase III/metabolism ; DNA Replication/*genetics ; DNA-Binding Proteins/metabolism ; Evolution, Molecular ; Genome, Human/*genetics ; Humans ; Models, Biological ; Mutagenesis/genetics ; Mutation/*genetics ; Protein Binding ; Saccharomyces cerevisiae/genetics ; Transcription Factors/metabolism
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    A self-organized biomechanical network drives shape changes during tissue morphogenesis (2015)
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    Publication Date: 2015-07-28
    Description: Tissue morphogenesis is orchestrated by cell shape changes. Forces required to power these changes are generated by non-muscle myosin II (MyoII) motor proteins pulling filamentous actin (F-actin). Actomyosin networks undergo cycles of assembly and disassembly (pulses) to cause cell deformations alternating with steps of stabilization to result in irreversible shape changes. Although this ratchet-like behaviour operates in a variety of contexts, the underlying mechanisms remain unclear. Here we investigate the role of MyoII regulation through the conserved Rho1-Rok pathway during Drosophila melanogaster germband extension. This morphogenetic process is powered by cell intercalation, which involves the shrinkage of junctions in the dorsal-ventral axis (vertical junctions) followed by junction extension in the anterior-posterior axis. While polarized flows of medial-apical MyoII pulses deform vertical junctions, MyoII enrichment on these junctions (planar polarity) stabilizes them. We identify two critical properties of MyoII dynamics that underlie stability and pulsatility: exchange kinetics governed by phosphorylation-dephosphorylation cycles of the MyoII regulatory light chain; and advection due to contraction of the motors on F-actin networks. Spatial control over MyoII exchange kinetics establishes two stable regimes of high and low dissociation rates, resulting in MyoII planar polarity. Pulsatility emerges at intermediate dissociation rates, enabling convergent advection of MyoII and its upstream regulators Rho1 GTP, Rok and MyoII phosphatase. Notably, pulsatility is not an outcome of an upstream Rho1 pacemaker. Rather, it is a self-organized system that involves positive and negative biomechanical feedback between MyoII advection and dissociation rates.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Munjal, Akankshi -- Philippe, Jean-Marc -- Munro, Edwin -- Lecuit, Thomas -- England -- Nature. 2015 Aug 20;524(7565):351-5. doi: 10.1038/nature14603. Epub 2015 Jul 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Aix Marseille Universite, CNRS, IBDM UMR7288, 13009 Marseille, France. ; Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26214737" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/metabolism ; Actomyosin/*metabolism ; Animals ; Cell Polarity ; *Cell Shape ; Drosophila Proteins/*metabolism ; Drosophila melanogaster/*cytology/*embryology/metabolism ; Female ; Kinetics ; Male ; *Morphogenesis ; Myosin Light Chains/metabolism ; Myosin Type II/metabolism ; Myosin-Light-Chain Phosphatase/metabolism ; Phosphorylation ; rho GTP-Binding Proteins/metabolism ; rho-Associated Kinases/metabolism
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    Universal allosteric mechanism for Galpha activation by GPCRs (2015)
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    Publication Date: 2015-07-07
    Description: G protein-coupled receptors (GPCRs) allosterically activate heterotrimeric G proteins and trigger GDP release. Given that there are approximately 800 human GPCRs and 16 different Galpha genes, this raises the question of whether a universal allosteric mechanism governs Galpha activation. Here we show that different GPCRs interact with and activate Galpha proteins through a highly conserved mechanism. Comparison of Galpha with the small G protein Ras reveals how the evolution of short segments that undergo disorder-to-order transitions can decouple regions important for allosteric activation from receptor binding specificity. This might explain how the GPCR-Galpha system diversified rapidly, while conserving the allosteric activation mechanism.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Flock, Tilman -- Ravarani, Charles N J -- Sun, Dawei -- Venkatakrishnan, A J -- Kayikci, Melis -- Tate, Christopher G -- Veprintsev, Dmitry B -- Babu, M Madan -- MC_U105185859/Medical Research Council/United Kingdom -- MC_U105197215/Medical Research Council/United Kingdom -- England -- Nature. 2015 Aug 13;524(7564):173-9. doi: 10.1038/nature14663. Epub 2015 Jul 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. ; 1] Laboratory of Biomolecular Research, Paul Scherrer Institut, 5232 Villigen, Switzerland [2] Department of Biology, ETH Zurich, 8039 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26147082" target="_blank"〉PubMed〈/a〉
    Keywords: *Allosteric Regulation ; Animals ; Binding Sites ; Computational Biology ; Conserved Sequence ; Enzyme Activation ; *Evolution, Molecular ; GTP-Binding Protein alpha Subunits/chemistry/genetics/*metabolism ; Genetic Engineering ; Guanosine Diphosphate/metabolism ; Humans ; Models, Molecular ; Mutation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, G-Protein-Coupled/chemistry/*metabolism ; Signal Transduction ; Substrate Specificity ; ras Proteins/chemistry/metabolism
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    Parched California (2015)
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    Publication Date: 2015-09-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2015 Sep 3;525(7567):5. doi: 10.1038/525005b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26333434" target="_blank"〉PubMed〈/a〉
    Keywords: Agricultural Irrigation/methods/trends ; Animals ; Birds ; California ; Droughts/*statistics & numerical data ; Ecology/methods/*trends ; *Ecosystem ; Fires ; Fishes ; Groundwater/analysis ; *Water Supply/analysis/statistics & numerical data ; Wetlands
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    Mechanical induction of the tumorigenic beta-catenin pathway by tumour growth pressure (2015)
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    Publication Date: 2015-05-15
    Description: The tumour microenvironment may contribute to tumorigenesis owing to mechanical forces such as fibrotic stiffness or mechanical pressure caused by the expansion of hyper-proliferative cells. Here we explore the contribution of the mechanical pressure exerted by tumour growth onto non-tumorous adjacent epithelium. In the early stage of mouse colon tumour development in the Notch(+)Apc(+/1638N) mouse model, we observed mechanistic pressure stress in the non-tumorous epithelial cells caused by hyper-proliferative adjacent crypts overexpressing active Notch, which is associated with increased Ret and beta-catenin signalling. We thus developed a method that allows the delivery of a defined mechanical pressure in vivo, by subcutaneously inserting a magnet close to the mouse colon. The implanted magnet generated a magnetic force on ultra-magnetic liposomes, stabilized in the mesenchymal cells of the connective tissue surrounding colonic crypts after intravenous injection. The magnetically induced pressure quantitatively mimicked the endogenous early tumour growth stress in the order of 1,200 Pa, without affecting tissue stiffness, as monitored by ultrasound strain imaging and shear wave elastography. The exertion of pressure mimicking that of tumour growth led to rapid Ret activation and downstream phosphorylation of beta-catenin on Tyr654, imparing its interaction with the E-cadherin in adherens junctions, and which was followed by beta-catenin nuclear translocation after 15 days. As a consequence, increased expression of beta-catenin-target genes was observed at 1 month, together with crypt enlargement accompanying the formation of early tumorous aberrant crypt foci. Mechanical activation of the tumorigenic beta-catenin pathway suggests unexplored modes of tumour propagation based on mechanical signalling pathways in healthy epithelial cells surrounding the tumour, which may contribute to tumour heterogeneity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fernandez-Sanchez, Maria Elena -- Barbier, Sandrine -- Whitehead, Joanne -- Bealle, Gaelle -- Michel, Aude -- Latorre-Ossa, Heldmuth -- Rey, Colette -- Fouassier, Laura -- Claperon, Audrey -- Brulle, Laura -- Girard, Elodie -- Servant, Nicolas -- Rio-Frio, Thomas -- Marie, Helene -- Lesieur, Sylviane -- Housset, Chantal -- Gennisson, Jean-Luc -- Tanter, Mickael -- Menager, Christine -- Fre, Silvia -- Robine, Sylvie -- Farge, Emmanuel -- England -- Nature. 2015 Jul 2;523(7558):92-5. doi: 10.1038/nature14329. Epub 2015 May 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Curie, Centre de Recherche, PSL Research University, CNRS UMR 168, Physicochimie Curie Mechanics and Genetics of Embryonic and Tumour Development, INSERM, Fondation Pierre-Gilles de Gennes, F-75005 Paris, France. ; UPMC, Sorbonne Universites, Laboratoire PHENIX Physico-chimie des Electrolytes et Nanosystemes Interfaciaux, CNRS UMR 8234, F-75005 Paris, France. ; Langevin Institut, Waves and Images ESPCI ParisTech, PSL Research University, CNRS UMR7587, Inserm U979. F-75005 Paris, France. ; Sorbonne Universites, UPMC and INSERM, UMR-S 938, CDR Saint-Antoine, F-75012 Paris, France. ; CNRS UMR3666/INSERM U1143, Endocytic Trafficking and Therapeutic Delivery, Institut Curie, Centre de Recherche, F-75005 Paris, France. ; Bioinformatic platform, U900, Institut Curie, MINES ParisTech, F-75005 Paris, France. ; Next-generation sequencing platform, Institut Curie, F-75005 Paris, France. ; CNRS UMR 8612, Laboratoire Physico-Chimie des Systemes Polyphases, Institut Galien Paris-Sud, LabEx LERMIT, Faculte de Pharmacie, Universite Paris-Sud, 92 296 Chatenay-Malabry, France. ; CNRS UMR 3215/INSERM U934, Unite de Genetique et Biologie du Developpement, Notch Signaling in Stem Cells and Tumors, Institut Curie, Centre de Recherche, F-75005 Paris, France. ; CNRS UMR144, Compartimentation et dynamique cellulaires, Morphogenesis and Cell Signalling Institut Curie, Centre de Recherche, F-75005 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25970250" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Animals ; Carcinogenesis/*pathology ; Colonic Neoplasms/*physiopathology ; Epithelial Cells/cytology/pathology ; Female ; Gene Expression Regulation, Neoplastic ; Magnets ; Male ; Metal Nanoparticles ; Mice ; Mice, Inbred C57BL ; Phosphorylation ; *Pressure ; Proto-Oncogene Proteins c-ret/metabolism ; Receptors, Notch/genetics/metabolism ; Signal Transduction ; *Tumor Microenvironment ; beta Catenin/*genetics/metabolism
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    eIF3 targets cell-proliferation messenger RNAs for translational activation or repression (2015)
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    Publication Date: 2015-04-08
    Description: Regulation of protein synthesis is fundamental for all aspects of eukaryotic biology by controlling development, homeostasis and stress responses. The 13-subunit, 800-kilodalton eukaryotic initiation factor 3 (eIF3) organizes initiation factor and ribosome interactions required for productive translation. However, current understanding of eIF3 function does not explain genetic evidence correlating eIF3 deregulation with tissue-specific cancers and developmental defects. Here we report the genome-wide discovery of human transcripts that interact with eIF3 using photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP). eIF3 binds to a highly specific program of messenger RNAs involved in cell growth control processes, including cell cycling, differentiation and apoptosis, via the mRNA 5' untranslated region. Surprisingly, functional analysis of the interaction between eIF3 and two mRNAs encoding the cell proliferation regulators c-JUN and BTG1 reveals that eIF3 uses different modes of RNA stem-loop binding to exert either translational activation or repression. Our findings illuminate a new role for eIF3 in governing a specialized repertoire of gene expression and suggest that binding of eIF3 to specific mRNAs could be targeted to control carcinogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603833/" 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/PMC4603833/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Amy S Y -- Kranzusch, Philip J -- Cate, Jamie H D -- P50 GM102706/GM/NIGMS NIH HHS/ -- S10 RR027303/RR/NCRR NIH HHS/ -- S10 RR029668/RR/NCRR NIH HHS/ -- S10RR025622/RR/NCRR NIH HHS/ -- S10RR027303/RR/NCRR NIH HHS/ -- S10RR029668/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jun 4;522(7554):111-4. doi: 10.1038/nature14267. Epub 2015 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular &Cell Biology, University of California, Berkeley, Berkeley, California 94720, USA [2] Center for RNA Systems Biology, University of California, Berkeley, Berkeley, California 94720, USA. ; 1] Department of Molecular &Cell Biology, University of California, Berkeley, Berkeley, California 94720, USA [2] Howard Hughes Medical Institute (HHMI), University of California, Berkeley, Berkeley, California 94720, USA. ; 1] Department of Molecular &Cell Biology, University of California, Berkeley, Berkeley, California 94720, USA [2] Center for RNA Systems Biology, University of California, Berkeley, Berkeley, California 94720, USA [3] Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, USA [4] Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25849773" target="_blank"〉PubMed〈/a〉
    Keywords: 5' Untranslated Regions/genetics ; Apoptosis ; Binding Sites ; Cell Differentiation ; Cell Line ; Cell Proliferation/genetics ; Cross-Linking Reagents ; *Down-Regulation ; Eukaryotic Initiation Factor-3/chemistry/*metabolism ; Humans ; Immunoprecipitation ; Neoplasm Proteins/metabolism ; Neoplasms/metabolism/pathology ; Organ Specificity ; *Peptide Chain Initiation, Translational ; Phenotype ; Proto-Oncogene Proteins c-jun/metabolism ; RNA, Messenger/*genetics/*metabolism ; Reproducibility of Results ; Ribonucleosides ; Ribosomes/metabolism ; Substrate Specificity ; Transcriptome
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    Computational design of co-assembling protein-DNA nanowires (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-09-04
    Description: Biomolecular self-assemblies are of great interest to nanotechnologists because of their functional versatility and their biocompatibility. Over the past decade, sophisticated single-component nanostructures composed exclusively of nucleic acids, peptides and proteins have been reported, and these nanostructures have been used in a wide range of applications, from drug delivery to molecular computing. Despite these successes, the development of hybrid co-assemblies of nucleic acids and proteins has remained elusive. Here we use computational protein design to create a protein-DNA co-assembling nanomaterial whose assembly is driven via non-covalent interactions. To achieve this, a homodimerization interface is engineered onto the Drosophila Engrailed homeodomain (ENH), allowing the dimerized protein complex to bind to two double-stranded DNA (dsDNA) molecules. By varying the arrangement of protein-binding sites on the dsDNA, an irregular bulk nanoparticle or a nanowire with single-molecule width can be spontaneously formed by mixing the protein and dsDNA building blocks. We characterize the protein-DNA nanowire using fluorescence microscopy, atomic force microscopy and X-ray crystallography, confirming that the nanowire is formed via the proposed mechanism. This work lays the foundation for the development of new classes of protein-DNA hybrid materials. Further applications can be explored by incorporating DNA origami, DNA aptamers and/or peptide epitopes into the protein-DNA framework presented here.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mou, Yun -- Yu, Jiun-Yann -- Wannier, Timothy M -- Guo, Chin-Lin -- Mayo, Stephen L -- England -- Nature. 2015 Sep 10;525(7568):230-3. doi: 10.1038/nature14874. Epub 2015 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA. ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA. ; Division of Engineering and Applied Science, California Institute of Technology, Pasadena, California 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26331548" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; *Computer Simulation ; Crystallization ; Crystallography, X-Ray ; DNA/*chemistry ; *Drug Design ; Homeodomain Proteins/chemistry/genetics/metabolism ; Microscopy, Atomic Force ; Microscopy, Fluorescence ; Models, Molecular ; Nanotechnology ; Nanowires/*chemistry ; Protein Multimerization ; Transcription Factors/chemistry/genetics/metabolism
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    Ecosystem services: Academies review insecticide harm (2015)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2015-04-10
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Neumann, Peter -- England -- Nature. 2015 Apr 9;520(7546):157. doi: 10.1038/520157a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Bee Health, University of Bern, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25855445" target="_blank"〉PubMed〈/a〉
    Keywords: Academies and Institutes ; Agriculture/methods ; Animals ; Bees/drug effects/physiology ; *Ecosystem ; Europe ; Insecticides/*adverse effects ; Pollination ; Receptors, Nicotinic/metabolism ; Risk Assessment
    Print ISSN: 0028-0836
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    Ecology. Mothers shape ecological communities (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-02-24
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dantzer, Ben -- New York, N.Y. -- Science. 2015 Feb 20;347(6224):822-3. doi: 10.1126/science.aaa6480.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Psychology and Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, MI 48109, USA. dantzer@umich.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25700499" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; *Competitive Behavior ; *Ecosystem ; Female ; Male ; *Maternal Behavior ; Songbirds/*physiology
    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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    Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    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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    ECOLOGY. NSF looks for new contractor to finish troubled observatory (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-12-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mervis, Jeffrey -- New York, N.Y. -- Science. 2015 Dec 18;350(6267):1454. doi: 10.1126/science.350.6267.1454.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26680170" target="_blank"〉PubMed〈/a〉
    Keywords: Contract Services/*economics ; Ecology/*economics ; *Ecosystem ; United States
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    FUNGAL SYMBIONTS. Global assessment of arbuscular mycorrhizal fungus diversity reveals very low endemism (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-09-01
    Description: The global biogeography of microorganisms remains largely unknown, in contrast to the well-studied diversity patterns of macroorganisms. We used arbuscular mycorrhizal (AM) fungus DNA from 1014 plant-root samples collected worldwide to determine the global distribution of these plant symbionts. We found that AM fungal communities reflected local environmental conditions and the spatial distance between sites. However, despite AM fungi apparently possessing limited dispersal ability, we found 93% of taxa on multiple continents and 34% on all six continents surveyed. This contrasts with the high spatial turnover of other fungal taxa and with the endemism displayed by plants at the global scale. We suggest that the biogeography of AM fungi is driven by unexpectedly efficient dispersal, probably via both abiotic and biotic vectors, including humans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Davison, J -- Moora, M -- Opik, M -- Adholeya, A -- Ainsaar, L -- Ba, A -- Burla, S -- Diedhiou, A G -- Hiiesalu, I -- Jairus, T -- Johnson, N C -- Kane, A -- Koorem, K -- Kochar, M -- Ndiaye, C -- Partel, M -- Reier, U -- Saks, U -- Singh, R -- Vasar, M -- Zobel, M -- New York, N.Y. -- Science. 2015 Aug 28;349(6251):970-3. doi: 10.1126/science.aab1161.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Ecology and Earth Sciences, University of Tartu, Lai 40, Tartu 51005, Estonia. ; Centre for Mycorrhizal Research, The Energy and Resources Institute (TERI), India Habitat Centre, Lodhi Road, New Delhi 110 003, India. ; Laboratoire des Symbioses Tropicales et Mediterraneennes, Unite Mixte de Recherche 113, Laboratoire de Biologie et Physiologie Vegetales, Faculte des Sciences Exactes et Naturelles, Universite des Antilles, BP 592, 97159, Pointe-a-Pitre, Guadeloupe (French West Indies). ; Laboratoire Commun de Microbiologie de l'Institut de Recherche pour le Developpement-Institut Senegalais de Recherches Agricoles-Universite Cheikh Anta Diop (UCAD), Departement de Biologie Vegetale, UCAD, BP 5005 Dakar, Senegal. ; Institute of Ecology and Earth Sciences, University of Tartu, Lai 40, Tartu 51005, Estonia. Institute of Botany, Czech Academy of Sciences, Dukelska 135, 379 01 Trebon, Czech Republic. ; School of Earth Sciences and Environmental Sustainability, Northern Arizona University, Flagstaff, AZ 86011-5694, USA. ; Institute of Ecology and Earth Sciences, University of Tartu, Lai 40, Tartu 51005, Estonia. Netherlands Institute of Ecology, Droevendaalsesteeg 10, 6708 PB Wageningen, Netherlands. ; TERI-Deakin Nano Biotechnology Centre, Biotechnology and Management of Bioresources Division, TERI, India Habitat Centre, Lodhi Road, New Delhi 110 003, India.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26315436" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biodiversity ; DNA, Fungal/analysis ; *Ecosystem ; Environment ; Humans ; *Mycorrhizae/genetics/isolation & purification/physiology ; Phylogeny ; Phylogeography ; Plant Roots/*microbiology ; *Symbiosis ; Water ; Wind
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    Structural biology. Mechanistic insight from the crystal structure of mitochondrial complex I (2015)
    American Association for the Advancement of Science (AAAS)
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    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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    METALLOPROTEINS. A tethered niacin-derived pincer complex with a nickel-carbon bond in lactate racemase (2015)
    American Association for the Advancement of Science (AAAS)
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    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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    Ecological feedbacks. Termite mounds can increase the robustness of dryland ecosystems to climatic change (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-02-07
    Description: Self-organized spatial vegetation patterning is widespread and has been described using models of scale-dependent feedback between plants and water on homogeneous substrates. As rainfall decreases, these models yield a characteristic sequence of patterns with increasingly sparse vegetation, followed by sudden collapse to desert. Thus, the final, spot-like pattern may provide early warning for such catastrophic shifts. In many arid ecosystems, however, termite nests impart substrate heterogeneity by altering soil properties, thereby enhancing plant growth. We show that termite-induced heterogeneity interacts with scale-dependent feedbacks to produce vegetation patterns at different spatial grains. Although the coarse-grained patterning resembles that created by scale-dependent feedback alone, it does not indicate imminent desertification. Rather, mound-field landscapes are more robust to aridity, suggesting that termites may help stabilize ecosystems under global change.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bonachela, Juan A -- Pringle, Robert M -- Sheffer, Efrat -- Coverdale, Tyler C -- Guyton, Jennifer A -- Caylor, Kelly K -- Levin, Simon A -- Tarnita, Corina E -- New York, N.Y. -- Science. 2015 Feb 6;347(6222):651-5. doi: 10.1126/science.1261487.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ 08544, USA. ; Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ 08544, USA. Mpala Research Centre, Post Office Box 555, Nanyuki, Kenya. ; Mpala Research Centre, Post Office Box 555, Nanyuki, Kenya. Department of Civil and Environmental Engineering, Princeton University, Princeton, NJ 08544, USA. ; Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ 08544, USA. Mpala Research Centre, Post Office Box 555, Nanyuki, Kenya. ctarnita@princeton.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25657247" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Climate Change ; Conservation of Natural Resources ; *Desert Climate ; *Ecosystem ; Feedback ; Isoptera/*physiology ; Models, Biological ; *Plant Development ; *Rain ; Soil ; *Water
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    Paleoanthropology. Late Pliocene fossiliferous sedimentary record and the environmental context of early Homo from Afar, Ethiopia (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-03-06
    Description: Sedimentary basins in eastern Africa preserve a record of continental rifting and contain important fossil assemblages for interpreting hominin evolution. However, the record of hominin evolution between 3 and 2.5 million years ago (Ma) is poorly documented in surface outcrops, particularly in Afar, Ethiopia. Here we present the discovery of a 2.84- to 2.58-million-year-old fossil and hominin-bearing sediments in the Ledi-Geraru research area of Afar, Ethiopia, that have produced the earliest record of the genus Homo. Vertebrate fossils record a faunal turnover indicative of more open and probably arid habitats than those reconstructed earlier in this region, which is in broad agreement with hypotheses addressing the role of environmental forcing in hominin evolution at this time. Geological analyses constrain depositional and structural models of Afar and date the LD 350-1 Homo mandible to 2.80 to 2.75 Ma.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DiMaggio, Erin N -- Campisano, Christopher J -- Rowan, John -- Dupont-Nivet, Guillaume -- Deino, Alan L -- Bibi, Faysal -- Lewis, Margaret E -- Souron, Antoine -- Garello, Dominique -- Werdelin, Lars -- Reed, Kaye E -- Arrowsmith, J Ramon -- New York, N.Y. -- Science. 2015 Mar 20;347(6228):1355-9. doi: 10.1126/science.aaa1415. Epub 2015 Mar 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Geosciences, Pennsylvania State University, University Park, PA 16802, USA. dimaggio@psu.edu kreed@asu.edu. ; Institute of Human Origins, School of Human Evolution and Social Change, Arizona State University, Tempe, AZ 85287, USA. ; CNRS Geosciences Rennes, Campus de Beaulieu, 35042 Rennes, France. ; Berkeley Geochronology Center, 2455 Ridge Road, Berkeley, CA 94709, USA. ; Museum fur Naturkunde, Leibniz Institute for Evolution and Biodiversity Science, Invalidenstrasse 43, 10115 Berlin, Germany. ; Biology Program, Stockton University, 101 Vera King Farris Drive, Galloway, NJ 08205, USA. ; Human Evolution Research Center, University of California, Berkeley, 3101 Valley Life Sciences Building, Berkeley, CA, 94720-3160, USA. ; School of Earth and Space Exploration, Arizona State University, Tempe, AZ 85287, USA. ; Swedish Museum of Natural History, Department of Palaeobiology, Box 50007, SE-10405 Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25739409" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; *Ecosystem ; Ethiopia ; Fossils ; *Geologic Sediments ; *Hominidae
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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