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  • Amino Acid Sequence
  • American Association for the Advancement of Science (AAAS)  (223)
  • Nature Publishing Group (NPG)  (165)
  • 2010-2014  (388)
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  • American Association for the Advancement of Science (AAAS)  (223)
  • Nature Publishing Group (NPG)  (165)
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Year
  • 1
    Publication Date: 2014-10-09
    Description: The human immunodeficiency virus type 1 (HIV-1) envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a post-fusion state. As the sole viral antigen on the HIV-1 virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.5 A resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22. This structure reveals the pre-fusion conformation of gp41, indicates rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition. Pre-fusion gp41 encircles amino- and carboxy-terminal strands of gp120 with four helices that form a membrane-proximal collar, fastened by insertion of a fusion peptide-proximal methionine into a gp41-tryptophan clasp. Spike rearrangements required for entry involve opening the clasp and expelling the termini. N-linked glycosylation and sequence-variable regions cover the pre-fusion closed spike; we used chronic cohorts to map the prevalence and location of effective HIV-1-neutralizing responses, which were distinguished by their recognition of N-linked glycan and tolerance for epitope-sequence variation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348022/" 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/PMC4348022/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pancera, Marie -- Zhou, Tongqing -- Druz, Aliaksandr -- Georgiev, Ivelin S -- Soto, Cinque -- Gorman, Jason -- Huang, Jinghe -- Acharya, Priyamvada -- Chuang, Gwo-Yu -- Ofek, Gilad -- Stewart-Jones, Guillaume B E -- Stuckey, Jonathan -- Bailer, Robert T -- Joyce, M Gordon -- Louder, Mark K -- Tumba, Nancy -- Yang, Yongping -- Zhang, Baoshan -- Cohen, Myron S -- Haynes, Barton F -- Mascola, John R -- Morris, Lynn -- Munro, James B -- Blanchard, Scott C -- Mothes, Walther -- Connors, Mark -- Kwong, Peter D -- AI0678501/AI/NIAID NIH HHS/ -- AI100645/AI/NIAID NIH HHS/ -- P01 GM056550/GM/NIGMS NIH HHS/ -- P01-GM56550/GM/NIGMS NIH HHS/ -- P30 AI050410/AI/NIAID NIH HHS/ -- R01 GM098859/GM/NIGMS NIH HHS/ -- R01-GM098859/GM/NIGMS NIH HHS/ -- R21 AI100696/AI/NIAID NIH HHS/ -- R21-AI100696/AI/NIAID NIH HHS/ -- UL1 TR000142/TR/NCATS NIH HHS/ -- UM1 AI100645/AI/NIAID NIH HHS/ -- ZIA AI005023-13/Intramural NIH HHS/ -- ZIA AI005024-13/Intramural NIH HHS/ -- England -- Nature. 2014 Oct 23;514(7523):455-61. doi: 10.1038/nature13808. Epub 2014 Oct 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Sandringham, Johannesburg 2131, South Africa. ; Departments of Medicine, Epidemiology, Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ; Duke University Human Vaccine Institute, Departments of Medicine, Surgery, Pediatrics and Immunology, Duke University School of Medicine, and the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery at Duke University, Durham, North Carolina 27710, USA. ; 1] Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Sandringham, Johannesburg 2131, South Africa [2] University of the Witwatersrand, Braamfontein, Johannesburg 2000, South Africa [3] Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban 4041, South Africa. ; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06536, USA. ; Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, New York 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25296255" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines/chemistry/immunology ; Amino Acid Sequence ; Antibodies, Neutralizing/immunology ; Cohort Studies ; Crystallography, X-Ray ; Genetic Variation ; Glycosylation ; HIV Antibodies/immunology ; HIV Envelope Protein gp120/*chemistry/genetics/*immunology ; HIV Envelope Protein gp41/*chemistry/genetics/*immunology ; HIV Infections/immunology ; Humans ; Immune Evasion ; Membrane Fusion ; Models, Molecular ; Molecular Sequence Data ; Polysaccharides/chemistry/immunology ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Subunits/chemistry/genetics/immunology ; Structural Homology, Protein ; Virus Internalization
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  • 2
    Publication Date: 2014-10-09
    Description: The neutralizing antibody response to influenza virus is dominated by antibodies that bind to the globular head of haemagglutinin, which undergoes a continuous antigenic drift, necessitating the re-formulation of influenza vaccines on an annual basis. Recently, several laboratories have described a new class of rare influenza-neutralizing antibodies that target a conserved site in the haemagglutinin stem. Most of these antibodies use the heavy-chain variable region VH1-69 gene, and structural data demonstrate that they bind to the haemagglutinin stem through conserved heavy-chain complementarity determining region (HCDR) residues. However, the VH1-69 antibodies are highly mutated and are produced by some but not all individuals, suggesting that several somatic mutations may be required for their development. To address this, here we characterize 197 anti-stem antibodies from a single donor, reconstruct the developmental pathways of several VH1-69 clones and identify two key elements that are required for the initial development of most VH1-69 antibodies: a polymorphic germline-encoded phenylalanine at position 54 and a conserved tyrosine at position 98 in HCDR3. Strikingly, in most cases a single proline to alanine mutation at position 52a in HCDR2 is sufficient to confer high affinity binding to the selecting H1 antigen, consistent with rapid affinity maturation. Surprisingly, additional favourable mutations continue to accumulate, increasing the breadth of reactivity and making both the initial mutations and phenylalanine at position 54 functionally redundant. These results define VH1-69 allele polymorphism, rearrangement of the VDJ gene segments and single somatic mutations as the three requirements for generating broadly neutralizing VH1-69 antibodies and reveal an unexpected redundancy in the affinity maturation process.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pappas, Leontios -- Foglierini, Mathilde -- Piccoli, Luca -- Kallewaard, Nicole L -- Turrini, Filippo -- Silacci, Chiara -- Fernandez-Rodriguez, Blanca -- Agatic, Gloria -- Giacchetto-Sasselli, Isabella -- Pellicciotta, Gabriele -- Sallusto, Federica -- Zhu, Qing -- Vicenzi, Elisa -- Corti, Davide -- Lanzavecchia, Antonio -- U19 AI-057266/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Dec 18;516(7531):418-22. doi: 10.1038/nature13764. Epub 2014 Oct 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Insitute for Research in Biomedicine, Universita della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland. ; Department of Infectious Diseases and Vaccines MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland 20878, USA. ; Viral Pathogens and Biosafety Unit, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. ; Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland. ; Unit of Preventive Medicine, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. ; 1] Insitute for Research in Biomedicine, Universita della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland [2] Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland [3]. ; 1] Insitute for Research in Biomedicine, Universita della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland [2] Insitute for Microbiology, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25296253" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Amino Acid Sequence ; Antibodies, Neutralizing/*genetics ; Cells, Cultured ; Complementarity Determining Regions/chemistry/*genetics ; Female ; Hemagglutinin Glycoproteins, Influenza Virus/immunology ; Humans ; Immunoglobulin Heavy Chains/genetics ; Influenza, Human/*immunology/virology ; Male ; Middle Aged ; Models, Molecular ; Mutation/*genetics ; Orthomyxoviridae/*immunology/metabolism ; Polymorphism, Genetic ; Protein Binding/genetics ; Protein Structure, Tertiary ; Young Adult
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  • 3
    Publication Date: 2014-12-10
    Description: The widespread reorganization of cellular architecture in mitosis is achieved through extensive protein phosphorylation, driven by the coordinated activation of a mitotic kinase network and repression of counteracting phosphatases. Phosphatase activity must subsequently be restored to promote mitotic exit. Although Cdc14 phosphatase drives this reversal in budding yeast, protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) activities have each been independently linked to mitotic exit control in other eukaryotes. Here we describe a mitotic phosphatase relay in which PP1 reactivation is required for the reactivation of both PP2A-B55 and PP2A-B56 to coordinate mitotic progression and exit in fission yeast. The staged recruitment of PP1 (the Dis2 isoform) to the regulatory subunits of the PP2A-B55 and PP2A-B56 (B55 also known as Pab1; B56 also known as Par1) holoenzymes sequentially activates each phosphatase. The pathway is blocked in early mitosis because the Cdk1-cyclin B kinase (Cdk1 also known as Cdc2) inhibits PP1 activity, but declining cyclin B levels later in mitosis permit PP1 to auto-reactivate. PP1 first reactivates PP2A-B55; this enables PP2A-B55 in turn to promote the reactivation of PP2A-B56 by dephosphorylating a PP1-docking site in PP2A-B56, thereby promoting the recruitment of PP1. PP1 recruitment to human, mitotic PP2A-B56 holoenzymes and the sequences of these conserved PP1-docking motifs suggest that PP1 regulates PP2A-B55 and PP2A-B56 activities in a variety of signalling contexts throughout eukaryotes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338534/" 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/PMC4338534/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grallert, Agnes -- Boke, Elvan -- Hagting, Anja -- Hodgson, Ben -- Connolly, Yvonne -- Griffiths, John R -- Smith, Duncan L -- Pines, Jonathon -- Hagan, Iain M -- 092096/Wellcome Trust/United Kingdom -- A13678/Cancer Research UK/United Kingdom -- A16406/Cancer Research UK/United Kingdom -- C147/A16406/Cancer Research UK/United Kingdom -- C29/A13678/Cancer Research UK/United Kingdom -- England -- Nature. 2015 Jan 1;517(7532):94-8. doi: 10.1038/nature14019. Epub 2014 Dec 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Division Group, CRUK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. ; The Gurdon Institute, Tennis Court Road, University of Cambridge, Cambridge, CB2 1QN, UK. ; Biological Mass Spectrometry, CRUK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25487150" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Binding Sites ; CDC2 Protein Kinase/metabolism ; Chromosome Segregation ; Conserved Sequence ; Cyclin B/metabolism ; Enzyme Activation ; HeLa Cells ; Holoenzymes/metabolism ; Humans ; Isoenzymes/metabolism ; *Mitosis ; Molecular Sequence Data ; Phosphorylation ; Protein Phosphatase 1/*metabolism ; Protein Phosphatase 2/chemistry/*metabolism ; Protein Subunits/chemistry/metabolism ; Schizosaccharomyces/*cytology/*enzymology ; Schizosaccharomyces pombe Proteins/chemistry/metabolism ; Signal Transduction
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  • 4
    Publication Date: 2014-04-12
    Description: Plant embryogenesis initiates with the establishment of an apical-basal axis; however, the molecular mechanisms accompanying this early event remain unclear. Here, we show that a small cysteine-rich peptide family is required for formation of the zygotic basal cell lineage and proembryo patterning in Arabidopsis. EMBRYO SURROUNDING FACTOR 1 (ESF1) peptides accumulate before fertilization in central cell gametes and thereafter in embryo-surrounding endosperm cells. Biochemical and structural analyses revealed cleavage of ESF1 propeptides to form biologically active mature peptides. Further, these peptides act in a non-cell-autonomous manner and synergistically with the receptor-like kinase SHORT SUSPENSOR to promote suspensor elongation through the YODA mitogen-activated protein kinase pathway. Our findings demonstrate that the second female gamete and its sexually derived endosperm regulate early embryonic patterning in flowering plants.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Costa, Liliana M -- Marshall, Eleanor -- Tesfaye, Mesfin -- Silverstein, Kevin A T -- Mori, Masashi -- Umetsu, Yoshitaka -- Otterbach, Sophie L -- Papareddy, Ranjith -- Dickinson, Hugh G -- Boutiller, Kim -- VandenBosch, Kathryn A -- Ohki, Shinya -- Gutierrez-Marcos, Jose F -- BB/F008082/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/L003023/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/L003023/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Apr 11;344(6180):168-72. doi: 10.1126/science.1243005.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Plant Sciences, University of Oxford, South Parks Road, OX1 3RB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24723605" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arabidopsis/*embryology/genetics ; Arabidopsis Proteins/chemistry/genetics/*metabolism ; *Body Patterning ; Endosperm/embryology/genetics ; Flowers/*embryology/genetics ; Gene Duplication ; Gene Expression Regulation, Developmental ; Gene Expression Regulation, Plant ; Gene Knockout Techniques ; Interleukin-1 Receptor-Associated Kinases/metabolism ; MAP Kinase Kinase Kinases/metabolism ; Molecular Sequence Data ; Peptides/chemistry/genetics/metabolism ; Seeds/*embryology/genetics
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  • 5
    Publication Date: 2014-09-23
    Description: Ribonucleotide reductase (RNR) supplies the balanced pools of deoxynucleotide triphosphates (dNTPs) necessary for DNA replication and maintenance of genomic integrity. RNR is subject to allosteric regulatory mechanisms in all eukaryotes, as well as to control by small protein inhibitors Sml1p and Spd1p in budding and fission yeast, respectively. Here, we show that the metazoan protein IRBIT forms a deoxyadenosine triphosphate (dATP)-dependent complex with RNR, which stabilizes dATP in the activity site of RNR and thus inhibits the enzyme. Formation of the RNR-IRBIT complex is regulated through phosphorylation of IRBIT, and ablation of IRBIT expression in HeLa cells causes imbalanced dNTP pools and altered cell cycle progression. We demonstrate a mechanism for RNR regulation in higher eukaryotes that acts by enhancing allosteric RNR inhibition by dATP.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arnaoutov, Alexei -- Dasso, Mary -- New York, N.Y. -- Science. 2014 Sep 19;345(6203):1512-5. doi: 10.1126/science.1251550.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Gene Regulation and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. arnaouta@mail.nih.gov. ; Laboratory of Gene Regulation and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25237103" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Amino Acid Sequence ; Catalytic Domain ; Deoxyadenine Nucleotides/*metabolism ; HeLa Cells ; Humans ; Immunoprecipitation ; Lectins, C-Type/genetics/*metabolism ; Membrane Proteins/genetics/*metabolism ; Molecular Sequence Data ; Phosphorylation ; Ribonucleotide Reductases/*antagonists & inhibitors/metabolism
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  • 6
    Publication Date: 2014-04-26
    Description: Using light to silence electrical activity in targeted cells is a major goal of optogenetics. Available optogenetic proteins that directly move ions to achieve silencing are inefficient, pumping only a single ion per photon across the cell membrane rather than allowing many ions per photon to flow through a channel pore. Building on high-resolution crystal-structure analysis, pore vestibule modeling, and structure-guided protein engineering, we designed and characterized a class of channelrhodopsins (originally cation-conducting) converted into chloride-conducting anion channels. These tools enable fast optical inhibition of action potentials and can be engineered to display step-function kinetics for stable inhibition, outlasting light pulses and for orders-of-magnitude-greater light sensitivity of inhibited cells. The resulting family of proteins defines an approach to more physiological, efficient, and sensitive optogenetic inhibition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096039/" 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/PMC4096039/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Berndt, Andre -- Lee, Soo Yeun -- Ramakrishnan, Charu -- Deisseroth, Karl -- R01 DA020794/DA/NIDA NIH HHS/ -- R01 MH075957/MH/NIMH NIH HHS/ -- R01 MH086373/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Apr 25;344(6182):420-4. doi: 10.1126/science.1252367.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24763591" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials ; Amino Acid Sequence ; Animals ; CA1 Region, Hippocampal/cytology ; CA3 Region, Hippocampal/cytology ; Chloride Channels/*chemistry/*metabolism ; Chlorides/*metabolism ; HEK293 Cells ; Humans ; Light ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Neurons/*physiology ; Optogenetics ; Patch-Clamp Techniques ; Protein Engineering ; Rats ; Rats, Sprague-Dawley ; Recombinant Fusion Proteins/chemistry/metabolism ; Rhodopsin/*chemistry/genetics/*metabolism
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  • 7
    Publication Date: 2014-03-08
    Description: The excitatory neurotransmitter glutamate induces modulatory actions via the metabotropic glutamate receptors (mGlus), which are class C G protein-coupled receptors (GPCRs). We determined the structure of the human mGlu1 receptor seven-transmembrane (7TM) domain bound to a negative allosteric modulator, FITM, at a resolution of 2.8 angstroms. The modulator binding site partially overlaps with the orthosteric binding sites of class A GPCRs but is more restricted than most other GPCRs. We observed a parallel 7TM dimer mediated by cholesterols, which suggests that signaling initiated by glutamate's interaction with the extracellular domain might be mediated via 7TM interactions within the full-length receptor dimer. A combination of crystallography, structure-activity relationships, mutagenesis, and full-length dimer modeling provides insights about the allosteric modulation and activation mechanism of class C GPCRs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991565/" 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/PMC3991565/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Huixian -- Wang, Chong -- Gregory, Karen J -- Han, Gye Won -- Cho, Hyekyung P -- Xia, Yan -- Niswender, Colleen M -- Katritch, Vsevolod -- Meiler, Jens -- Cherezov, Vadim -- Conn, P Jeffrey -- Stevens, Raymond C -- P50 GM073197/GM/NIGMS NIH HHS/ -- R01 DK097376/DK/NIDDK NIH HHS/ -- R01 GM080403/GM/NIGMS NIH HHS/ -- R01 GM099842/GM/NIGMS NIH HHS/ -- R01 MH062646/MH/NIMH NIH HHS/ -- R01 MH090192/MH/NIMH NIH HHS/ -- R01 NS031373/NS/NINDS NIH HHS/ -- R21 NS078262/NS/NINDS NIH HHS/ -- R37 NS031373/NS/NINDS NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Apr 4;344(6179):58-64. doi: 10.1126/science.1249489. Epub 2014 Mar 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24603153" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Allosteric Site ; Amino Acid Sequence ; Benzamides/*chemistry/*metabolism ; Binding Sites ; Cholesterol ; Crystallography, X-Ray ; Humans ; Hydrophobic and Hydrophilic Interactions ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Protein Conformation ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, Metabotropic Glutamate/*chemistry/*metabolism ; Structure-Activity Relationship ; Thiazoles/*chemistry/*metabolism
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  • 8
    Publication Date: 2014-03-22
    Description: The development of cells specialized for water conduction or support is a striking innovation of plants that has enabled them to colonize land. The NAC transcription factors regulate the differentiation of these cells in vascular plants. However, the path by which plants with these cells have evolved from their nonvascular ancestors is unclear. We investigated genes of the moss Physcomitrella patens that encode NAC proteins. Loss-of-function mutants formed abnormal water-conducting and supporting cells, as well as malformed sporophyte cells, and overexpression induced ectopic differentiation of water-conducting-like cells. Our results show conservation of transcriptional regulation and cellular function between moss and Arabidopsis thaliana water-conducting cells. The conserved genetic basis suggests roles for NAC proteins in the adaptation of plants to land.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Bo -- Ohtani, Misato -- Yamaguchi, Masatoshi -- Toyooka, Kiminori -- Wakazaki, Mayumi -- Sato, Mayuko -- Kubo, Minoru -- Nakano, Yoshimi -- Sano, Ryosuke -- Hiwatashi, Yuji -- Murata, Takashi -- Kurata, Tetsuya -- Yoneda, Arata -- Kato, Ko -- Hasebe, Mitsuyasu -- Demura, Taku -- New York, N.Y. -- Science. 2014 Mar 28;343(6178):1505-8. doi: 10.1126/science.1248417. Epub 2014 Mar 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24652936" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological/*genetics ; Amino Acid Sequence ; Arabidopsis/genetics/*physiology ; Bryopsida/genetics/*physiology ; *Gene Expression Regulation, Plant ; Genetic Loci ; Genome, Plant ; Molecular Sequence Data ; Plant Proteins/genetics/*physiology ; Plant Stems/growth & development ; Trans-Activators/genetics/*physiology ; Transcription, Genetic ; Water/*physiology
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  • 9
    Publication Date: 2014-08-26
    Description: Sensory systems define an animal's capacity for perception and can evolve to promote survival in new environmental niches. We have uncovered a noncanonical mechanism for sweet taste perception that evolved in hummingbirds since their divergence from insectivorous swifts, their closest relatives. We observed the widespread absence in birds of an essential subunit (T1R2) of the only known vertebrate sweet receptor, raising questions about how specialized nectar feeders such as hummingbirds sense sugars. Receptor expression studies revealed that the ancestral umami receptor (the T1R1-T1R3 heterodimer) was repurposed in hummingbirds to function as a carbohydrate receptor. Furthermore, the molecular recognition properties of T1R1-T1R3 guided taste behavior in captive and wild hummingbirds. We propose that changing taste receptor function enabled hummingbirds to perceive and use nectar, facilitating the massive radiation of hummingbird species.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302410/" 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/PMC4302410/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baldwin, Maude W -- Toda, Yasuka -- Nakagita, Tomoya -- O'Connell, Mary J -- Klasing, Kirk C -- Misaka, Takumi -- Edwards, Scott V -- Liberles, Stephen D -- R01 DC013289/DC/NIDCD NIH HHS/ -- R01DC013289/DC/NIDCD NIH HHS/ -- New York, N.Y. -- Science. 2014 Aug 22;345(6199):929-33. doi: 10.1126/science.1255097.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Organismic and Evolutionary Biology, Harvard University, and Museum of Comparative Zoology, Cambridge, MA 02138, USA. maudebaldwin@gmail.com stephen_liberles@hms.harvard.edu. ; Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan. ; Bioinformatics and Molecular Evolution Group, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland. ; Department of Animal Science, University of California, Davis, Davis, CA 95616, USA. ; Department of Organismic and Evolutionary Biology, Harvard University, and Museum of Comparative Zoology, Cambridge, MA 02138, USA. ; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. maudebaldwin@gmail.com stephen_liberles@hms.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25146290" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; *Evolution, Molecular ; Mice ; Molecular Sequence Data ; Plant Nectar ; Protein Structure, Tertiary ; Receptors, G-Protein-Coupled/chemistry/classification/*genetics ; Taste/*physiology ; Taste Perception/genetics/*physiology
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  • 10
    Publication Date: 2014-04-26
    Description: The hierarchical packaging of eukaryotic chromatin plays a central role in transcriptional regulation and other DNA-related biological processes. Here, we report the 11-angstrom-resolution cryogenic electron microscopy (cryo-EM) structures of 30-nanometer chromatin fibers reconstituted in the presence of linker histone H1 and with different nucleosome repeat lengths. The structures show a histone H1-dependent left-handed twist of the repeating tetranucleosomal structural units, within which the four nucleosomes zigzag back and forth with a straight linker DNA. The asymmetric binding and the location of histone H1 in chromatin play a role in the formation of the 30-nanometer fiber. Our results provide mechanistic insights into how nucleosomes compact into higher-order chromatin fibers.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Song, Feng -- Chen, Ping -- Sun, Dapeng -- Wang, Mingzhu -- Dong, Liping -- Liang, Dan -- Xu, Rui-Ming -- Zhu, Ping -- Li, Guohong -- New York, N.Y. -- Science. 2014 Apr 25;344(6182):376-80. doi: 10.1126/science.1251413.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24763583" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Chromatin/chemistry/metabolism/*ultrastructure ; Cryoelectron Microscopy ; DNA/chemistry/*ultrastructure ; Histones/*chemistry/metabolism ; Imaging, Three-Dimensional ; Models, Molecular ; Molecular Sequence Data ; Nucleic Acid Conformation ; Nucleosomes/*ultrastructure ; Protein Conformation ; Recombinant Proteins/chemistry/metabolism ; Xenopus Proteins/chemistry ; Xenopus laevis
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  • 11
    Publication Date: 2014-10-18
    Description: Nitrogen (N) is a critical nutrient for plants but is often distributed unevenly in the soil. Plants therefore have evolved a systemic mechanism by which N starvation on one side of the root system leads to a compensatory and increased nitrate uptake on the other side. Here, we study the molecular systems that support perception of N and the long-distance signaling needed to alter root development. Rootlets starved of N secrete small peptides that are translocated to the shoot and received by two leucine-rich repeat receptor kinases (LRR-RKs). Arabidopsis plants deficient in this pathway show growth retardation accompanied with N-deficiency symptoms. Thus, signaling from the root to the shoot helps the plant adapt to fluctuations in local N availability.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tabata, Ryo -- Sumida, Kumiko -- Yoshii, Tomoaki -- Ohyama, Kentaro -- Shinohara, Hidefumi -- Matsubayashi, Yoshikatsu -- New York, N.Y. -- Science. 2014 Oct 17;346(6207):343-6. doi: 10.1126/science.1257800.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan. ; Department of Applied Molecular Biosciences, Graduate School of Bio-Agricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan. ; Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan. matsu@bio.nagoya-u.ac.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25324386" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arabidopsis/genetics/*growth & development/metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Molecular Sequence Data ; Nitrogen/*metabolism ; Peptides/*metabolism ; Plant Roots/genetics/*growth & development/metabolism ; Plant Shoots/genetics/*growth & development/metabolism ; Receptors, Peptide/genetics/*metabolism ; Signal Transduction
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  • 12
    Publication Date: 2014-07-26
    Description: Proteins that cap the ends of the actin filament are essential regulators of cytoskeleton dynamics. Whereas several proteins cap the rapidly growing barbed end, tropomodulin (Tmod) is the only protein known to cap the slowly growing pointed end. The lack of structural information severely limits our understanding of Tmod's capping mechanism. We describe crystal structures of actin complexes with the unstructured amino-terminal and the leucine-rich repeat carboxy-terminal domains of Tmod. The structures and biochemical analysis of structure-inspired mutants showed that one Tmod molecule interacts with three actin subunits at the pointed end, while also contacting two tropomyosin molecules on each side of the filament. We found that Tmod achieves high-affinity binding through several discrete low-affinity interactions, which suggests a mechanism for controlled subunit exchange at the pointed end.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367809/" 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/PMC4367809/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rao, Jampani Nageswara -- Madasu, Yadaiah -- Dominguez, Roberto -- GM-0080/GM/NIGMS NIH HHS/ -- R01 GM073791/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Jul 25;345(6195):463-7. doi: 10.1126/science.1256159.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ; Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. droberto@mail.med.upenn.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25061212" target="_blank"〉PubMed〈/a〉
    Keywords: Actin Cytoskeleton/*chemistry ; Actins/*chemistry ; Amino Acid Sequence ; Animals ; Crystallography, X-Ray ; Humans ; Molecular Sequence Data ; Mutation ; Protein Binding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Rabbits ; Tropomodulin/*chemistry/genetics
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  • 13
    Publication Date: 2014-01-18
    Description: Transcription factors (TFs) are key players in evolution. Changes affecting their function can yield novel life forms but may also have deleterious effects. Consequently, gene duplication events that release one gene copy from selective pressure are thought to be the common mechanism by which TFs acquire new activities. Here, we show that LEAFY, a major regulator of flower development and cell division in land plants, underwent changes to its DNA binding specificity, even though plant genomes generally contain a single copy of the LEAFY gene. We examined how these changes occurred at the structural level and identify an intermediate LEAFY form in hornworts that appears to adopt all different specificities. This promiscuous intermediate could have smoothed the evolutionary transitions, thereby allowing LEAFY to evolve new binding specificities while remaining a single-copy gene.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sayou, Camille -- Monniaux, Marie -- Nanao, Max H -- Moyroud, Edwige -- Brockington, Samuel F -- Thevenon, Emmanuel -- Chahtane, Hicham -- Warthmann, Norman -- Melkonian, Michael -- Zhang, Yong -- Wong, Gane Ka-Shu -- Weigel, Detlef -- Parcy, Francois -- Dumas, Renaud -- New York, N.Y. -- Science. 2014 Feb 7;343(6171):645-8. doi: 10.1126/science.1248229. Epub 2014 Jan 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CNRS, Laboratoire de Physiologie Cellulaire et Vegetale (LPCV), UMR 5168, 38054 Grenoble, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24436181" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arabidopsis Proteins/chemistry/classification/genetics ; DNA, Plant/*chemistry ; DNA-Binding Proteins/*chemistry/classification/*genetics ; Electrophoretic Mobility Shift Assay ; *Evolution, Molecular ; Gene Dosage ; Molecular Sequence Data ; Mutation ; Phylogeny ; Plant Proteins/*chemistry/classification/*genetics ; Protein Binding/genetics ; Protein Structure, Tertiary ; Species Specificity ; Transcription Factors/chemistry/classification/genetics
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  • 14
    Publication Date: 2014-07-12
    Description: Heterosexual transmission of HIV-1 typically results in one genetic variant establishing systemic infection. We compared, for 137 linked transmission pairs, the amino acid sequences encoded by non-envelope genes of viruses in both partners and demonstrate a selection bias for transmission of residues that are predicted to confer increased in vivo fitness on viruses in the newly infected, immunologically naive recipient. Although tempered by transmission risk factors, such as donor viral load, genital inflammation, and recipient gender, this selection bias provides an overall transmission advantage for viral quasispecies that are dominated by viruses with high in vivo fitness. Thus, preventative or therapeutic approaches that even marginally reduce viral fitness may lower the overall transmission rates and offer long-term benefits even upon successful transmission.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289910/" 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/PMC4289910/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Carlson, Jonathan M -- Schaefer, Malinda -- Monaco, Daniela C -- Batorsky, Rebecca -- Claiborne, Daniel T -- Prince, Jessica -- Deymier, Martin J -- Ende, Zachary S -- Klatt, Nichole R -- DeZiel, Charles E -- Lin, Tien-Ho -- Peng, Jian -- Seese, Aaron M -- Shapiro, Roger -- Frater, John -- Ndung'u, Thumbi -- Tang, Jianming -- Goepfert, Paul -- Gilmour, Jill -- Price, Matt A -- Kilembe, William -- Heckerman, David -- Goulder, Philip J R -- Allen, Todd M -- Allen, Susan -- Hunter, Eric -- 2P51RR000165-51/RR/NCRR NIH HHS/ -- G108/626/Medical Research Council/United Kingdom -- OD P51OD11132/OD/NIH HHS/ -- P01-AI074415/AI/NIAID NIH HHS/ -- P30 AI050409/AI/NIAID NIH HHS/ -- P51 OD010425/OD/NIH HHS/ -- P51 OD011132/OD/NIH HHS/ -- P51RR165/RR/NCRR NIH HHS/ -- R01 AI064060/AI/NIAID NIH HHS/ -- R01 AI64060/AI/NIAID NIH HHS/ -- R37 AI051231/AI/NIAID NIH HHS/ -- R37 AI51231/AI/NIAID NIH HHS/ -- T32 AI007387/AI/NIAID NIH HHS/ -- T32-AI007387/AI/NIAID NIH HHS/ -- U01 AI 66454/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Jul 11;345(6193):1254031. doi: 10.1126/science.1254031. Epub 2014 Jul 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Microsoft Research, Redmond, WA 98052, USA. carlson@microsoft.com ehunte4@emory.edu. ; Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA. ; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02114, USA. ; Microsoft Research, Redmond, WA 98052, USA. ; Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. ; Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX1 7BN, UK. National Institute of Health Research, Oxford Biomedical Research Centre, Oxford OX3 7LE, UK. Oxford Martin School, University of Oxford, Oxford OX1 3BD, UK. ; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02114, USA. HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban 4013, South Africa. KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban 4001, South Africa. Max Planck Institute for Infection Biology, D-10117 Berlin, Germany. ; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. ; International AIDS Vaccine Initiative, London SW10 9NH, UK. Imperial College of Science Technology and Medicine, London SW10 9NH, UK. ; International AIDS Vaccine Initiative, San Francisco, CA 94105, USA. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94105, USA. ; Rwanda-Zambia HIV Research Group: Zambia-Emory HIV Research Project, Lusaka, Zambia. ; Microsoft Research, Los Angeles, CA 98117, USA. ; HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban 4013, South Africa. Department of Paediatrics, University of Oxford, Oxford OX1 3SY, UK. ; Rwanda-Zambia HIV Research Group: Zambia-Emory HIV Research Project, Lusaka, Zambia. Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA. Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA. ; International AIDS Vaccine Initiative, San Francisco, CA 94105, USA. Microsoft Research, Los Angeles, CA 98117, USA. Department of Paediatrics, University of Oxford, Oxford OX1 3SY, UK. ; Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA. Rwanda-Zambia HIV Research Group: Zambia-Emory HIV Research Project, Lusaka, Zambia. Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA. carlson@microsoft.com ehunte4@emory.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25013080" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Consensus Sequence ; DNA Mutational Analysis ; Disease Transmission, Infectious/statistics & numerical data ; Female ; HIV Infections/*transmission ; HIV-1/*genetics ; *Heterosexuality ; High-Throughput Nucleotide Sequencing ; Human Immunodeficiency Virus Proteins/genetics ; Humans ; Male ; Models, Statistical ; Molecular Sequence Data ; Point Mutation ; Risk Factors ; *Selection, Genetic ; Viral Load
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  • 15
    Publication Date: 2014-03-05
    Description: Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01-12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30-38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395007/" 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/PMC4395007/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Doria-Rose, Nicole A -- Schramm, Chaim A -- Gorman, Jason -- Moore, Penny L -- Bhiman, Jinal N -- DeKosky, Brandon J -- Ernandes, Michael J -- Georgiev, Ivelin S -- Kim, Helen J -- Pancera, Marie -- Staupe, Ryan P -- Altae-Tran, Han R -- Bailer, Robert T -- Crooks, Ema T -- Cupo, Albert -- Druz, Aliaksandr -- Garrett, Nigel J -- Hoi, Kam H -- Kong, Rui -- Louder, Mark K -- Longo, Nancy S -- McKee, Krisha -- Nonyane, Molati -- O'Dell, Sijy -- Roark, Ryan S -- Rudicell, Rebecca S -- Schmidt, Stephen D -- Sheward, Daniel J -- Soto, Cinque -- Wibmer, Constantinos Kurt -- Yang, Yongping -- Zhang, Zhenhai -- NISC Comparative Sequencing Program -- Mullikin, James C -- Binley, James M -- Sanders, Rogier W -- Wilson, Ian A -- Moore, John P -- Ward, Andrew B -- Georgiou, George -- Williamson, Carolyn -- Abdool Karim, Salim S -- Morris, Lynn -- Kwong, Peter D -- Shapiro, Lawrence -- Mascola, John R -- P01 AI082362/AI/NIAID NIH HHS/ -- R01 AI100790/AI/NIAID NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2014 May 1;509(7498):55-62. doi: 10.1038/nature13036. Epub 2014 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA [2]. ; 1] Department of Biochemistry, Columbia University, New York, New York 10032, USA [2]. ; 1] Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Johannesburg, 2131, South Africa [2] Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2050, South Africa [3] Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, 4013, South Africa [4]. ; 1] Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Johannesburg, 2131, South Africa [2] Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2050, South Africa. ; Department of Chemical Engineering, University of Texas at Austin, Austin, Texas 78712, USA. ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA [2] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA [3] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA. ; Torrey Pines Institute, San Diego, California 92037, USA. ; Weill Medical College of Cornell University, New York, New York 10065, USA. ; Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, 4013, South Africa. ; Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA. ; Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Johannesburg, 2131, South Africa. ; Institute of Infectious Diseases and Molecular Medicine, Division of Medical Virology, University of Cape Town and NHLS, Cape Town 7701, South Africa. ; Department of Biochemistry, Columbia University, New York, New York 10032, USA. ; 1] NISC Comparative Sequencing program, National Institutes of Health, Bethesda, Maryland 20892, USA [2] NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Department of Medical Microbiology, Academic Medical Center, Amsterdam 1105 AZ, Netherlands. ; 1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA [2] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA [3] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [4] Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA. ; 1] Department of Chemical Engineering, University of Texas at Austin, Austin, Texas 78712, USA [2] Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA [3] Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas 78712, USA. ; 1] Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, 4013, South Africa [2] Institute of Infectious Diseases and Molecular Medicine, Division of Medical Virology, University of Cape Town and NHLS, Cape Town 7701, South Africa. ; 1] Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, 4013, South Africa [2] Department of Epidemiology, Columbia University, New York, New York 10032, USA. ; 1] Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Johannesburg, 2131, South Africa [2] Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2050, South Africa [3] Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, 4013, South Africa. ; 1] Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA [2] Department of Biochemistry, Columbia University, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24590074" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines/chemistry/immunology ; Amino Acid Sequence ; Antibodies, Neutralizing/chemistry/genetics/*immunology/isolation & purification ; Antibody Affinity/genetics/immunology ; Antigens, CD4/immunology/metabolism ; B-Lymphocytes/cytology/immunology/metabolism ; Binding Sites/immunology ; Cell Lineage ; Complementarity Determining Regions/chemistry/genetics/immunology ; Epitope Mapping ; Epitopes, B-Lymphocyte/chemistry/immunology ; Evolution, Molecular ; HIV Antibodies/chemistry/genetics/*immunology/isolation & purification ; HIV Envelope Protein gp160/*chemistry/*immunology ; HIV Infections/immunology ; HIV-1/chemistry/immunology ; Humans ; Models, Molecular ; Molecular Sequence Data ; Neutralization Tests ; Protein Structure, Tertiary ; Somatic Hypermutation, Immunoglobulin/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 16
    Publication Date: 2014-02-28
    Description: Nitrate is a primary nutrient for plant growth, but its levels in soil can fluctuate by several orders of magnitude. Previous studies have identified Arabidopsis NRT1.1 as a dual-affinity nitrate transporter that can take up nitrate over a wide range of concentrations. The mode of action of NRT1.1 is controlled by phosphorylation of a key residue, Thr 101; however, how this post-translational modification switches the transporter between two affinity states remains unclear. Here we report the crystal structure of unphosphorylated NRT1.1, which reveals an unexpected homodimer in the inward-facing conformation. In this low-affinity state, the Thr 101 phosphorylation site is embedded in a pocket immediately adjacent to the dimer interface, linking the phosphorylation status of the transporter to its oligomeric state. Using a cell-based fluorescence resonance energy transfer assay, we show that functional NRT1.1 dimerizes in the cell membrane and that the phosphomimetic mutation of Thr 101 converts the protein into a monophasic high-affinity transporter by structurally decoupling the dimer. Together with analyses of the substrate transport tunnel, our results establish a phosphorylation-controlled dimerization switch that allows NRT1.1 to uptake nitrate with two distinct affinity modes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968801/" 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/PMC3968801/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sun, Ji -- Bankston, John R -- Payandeh, Jian -- Hinds, Thomas R -- Zagotta, William N -- Zheng, Ning -- NS074545/NS/NINDS NIH HHS/ -- R01EY10329/EY/NEI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Mar 6;507(7490):73-7. doi: 10.1038/nature13074. Epub 2014 Feb 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, Box 357280, University of Washington, Seattle, Washington 98195, USA. ; Department of Physiology and Biophysics, Box 357290, University of Washington, Seattle, Washington 98195, USA. ; 1] Department of Pharmacology, Box 357280, University of Washington, Seattle, Washington 98195, USA [2] Department of Structural Biology, Genentech Inc., South San Francisco, California 94080, USA. ; 1] Department of Pharmacology, Box 357280, University of Washington, Seattle, Washington 98195, USA [2] Howard Hughes Medical Institute, Box 357280, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24572362" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Anion Transport Proteins/*chemistry/genetics/metabolism ; Arabidopsis/*chemistry/genetics ; Binding Sites ; Biological Transport ; Cell Membrane/chemistry/metabolism ; Crystallography, X-Ray ; Fluorescence Resonance Energy Transfer ; Models, Biological ; Models, Molecular ; Molecular Sequence Data ; Mutation/genetics ; Nitrates/chemistry/metabolism ; Phosphorylation ; Phosphothreonine/chemistry/metabolism ; Plant Proteins/*chemistry/genetics/metabolism ; *Protein Multimerization ; Protein Structure, Quaternary ; Protons ; Structure-Activity Relationship
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  • 17
    Publication Date: 2014-08-15
    Description: Neurotransmitter-gated ion channels of the Cys-loop receptor family mediate fast neurotransmission throughout the nervous system. The molecular processes of neurotransmitter binding, subsequent opening of the ion channel and ion permeation remain poorly understood. Here we present the X-ray structure of a mammalian Cys-loop receptor, the mouse serotonin 5-HT3 receptor, at 3.5 A resolution. The structure of the proteolysed receptor, made up of two fragments and comprising part of the intracellular domain, was determined in complex with stabilizing nanobodies. The extracellular domain reveals the detailed anatomy of the neurotransmitter binding site capped by a nanobody. The membrane domain delimits an aqueous pore with a 4.6 A constriction. In the intracellular domain, a bundle of five intracellular helices creates a closed vestibule where lateral portals are obstructed by loops. This 5-HT3 receptor structure, revealing part of the intracellular domain, expands the structural basis for understanding the operating mechanism of mammalian Cys-loop receptors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hassaine, Gherici -- Deluz, Cedric -- Grasso, Luigino -- Wyss, Romain -- Tol, Menno B -- Hovius, Ruud -- Graff, Alexandra -- Stahlberg, Henning -- Tomizaki, Takashi -- Desmyter, Aline -- Moreau, Christophe -- Li, Xiao-Dan -- Poitevin, Frederic -- Vogel, Horst -- Nury, Hugues -- England -- Nature. 2014 Aug 21;512(7514):276-81. doi: 10.1038/nature13552. Epub 2014 Aug 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Laboratory of Physical Chemistry of Polymers and Membranes, Ecole Polytechnique Federale de Lausanne, CH-1015 Lausanne, Switzerland [2] [3] Theranyx, 163 Avenue de Luminy, 13288 Marseille, France. ; 1] Laboratory of Physical Chemistry of Polymers and Membranes, Ecole Polytechnique Federale de Lausanne, CH-1015 Lausanne, Switzerland [2]. ; Laboratory of Physical Chemistry of Polymers and Membranes, Ecole Polytechnique Federale de Lausanne, CH-1015 Lausanne, Switzerland. ; Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, CH-4058 Basel, Switzerland. ; Swiss Light Source, Paul Scherrer Institute, CH-5234 Villigen, Switzerland. ; Architecture et Fonction des Macromolecules Biologiques, CNRS UMR 7257 and Universite Aix-Marseille, F-13288 Marseille, France. ; 1] Universite Grenoble Alpes, IBS, F-38000 Grenoble, France [2] CNRS, IBS, F-38000 Grenoble, France [3] CEA, DSV, IBS, F-38000 Grenoble, France. ; Laboratory of Biomolecular Research, Paul Scherrer Institute, CH-5232 Villigen, Switzerland. ; Unite de Dynamique Structurale des Macromolecules, Institut Pasteur, CNRS UMR3528, F-75015 Paris, France. ; 1] Laboratory of Physical Chemistry of Polymers and Membranes, Ecole Polytechnique Federale de Lausanne, CH-1015 Lausanne, Switzerland [2] Universite Grenoble Alpes, IBS, F-38000 Grenoble, France [3] CNRS, IBS, F-38000 Grenoble, France [4] CEA, DSV, IBS, F-38000 Grenoble, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119048" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Binding Sites ; Crystallography, X-Ray ; Mice ; Models, Molecular ; Molecular Sequence Data ; Neurotransmitter Agents/metabolism ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Receptors, Serotonin, 5-HT3/*chemistry/metabolism
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  • 18
    Publication Date: 2014-01-28
    Description: H2A.Z is an essential histone variant implicated in the regulation of key nuclear events. However, the metazoan chaperones responsible for H2A.Z deposition and its removal from chromatin remain unknown. Here we report the identification and characterization of the human protein ANP32E as a specific H2A.Z chaperone. We show that ANP32E is a member of the presumed H2A.Z histone-exchange complex p400/TIP60. ANP32E interacts with a short region of the docking domain of H2A.Z through a new motif termed H2A.Z interacting domain (ZID). The 1.48 A resolution crystal structure of the complex formed between the ANP32E-ZID and the H2A.Z/H2B dimer and biochemical data support an underlying molecular mechanism for H2A.Z/H2B eviction from the nucleosome and its stabilization by ANP32E through a specific extension of the H2A.Z carboxy-terminal alpha-helix. Finally, analysis of H2A.Z localization in ANP32E(-/-) cells by chromatin immunoprecipitation followed by sequencing shows genome-wide enrichment, redistribution and accumulation of H2A.Z at specific chromatin control regions, in particular at enhancers and insulators.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Obri, Arnaud -- Ouararhni, Khalid -- Papin, Christophe -- Diebold, Marie-Laure -- Padmanabhan, Kiran -- Marek, Martin -- Stoll, Isabelle -- Roy, Ludovic -- Reilly, Patrick T -- Mak, Tak W -- Dimitrov, Stefan -- Romier, Christophe -- Hamiche, Ali -- England -- Nature. 2014 Jan 30;505(7485):648-53. doi: 10.1038/nature12922. Epub 2014 Jan 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Departement de Genomique Fonctionnelle et Cancer, Institut de Genetique et Biologie Moleculaire et Cellulaire (IGBMC), Universite de Strasbourg, CNRS, INSERM, 1 rue Laurent Fries, B.P. 10142, 67404 Illkirch Cedex, France [2]. ; Departement de Biologie Structurale Integrative, Institut de Genetique et Biologie Moleculaire et Cellulaire (IGBMC), Universite de Strasbourg, CNRS, INSERM, 1 rue Laurent Fries, B.P. 10142, 67404 Illkirch Cedex, France. ; Equipe labelisee Ligue contre le Cancer, INSERM/Universite Joseph Fourier , Institut Albert Bonniot, U823, Site Sante-BP 170, 38042 Grenoble Cedex 9, France. ; Departement de Genomique Fonctionnelle et Cancer, Institut de Genetique et Biologie Moleculaire et Cellulaire (IGBMC), Universite de Strasbourg, CNRS, INSERM, 1 rue Laurent Fries, B.P. 10142, 67404 Illkirch Cedex, France. ; Laboratory of Inflammation Biology, Division of Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore. ; 1] Laboratory of Inflammation Biology, Division of Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore [2] The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24463511" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cell Line ; Cell Nucleus/chemistry/metabolism ; Chromatin/*chemistry/genetics/*metabolism ; Chromatin Immunoprecipitation ; Crystallography, X-Ray ; DNA/genetics/metabolism ; Genome, Human/genetics ; Histones/chemistry/isolation & purification/*metabolism ; Humans ; Models, Molecular ; Molecular Chaperones/chemistry/*metabolism ; Molecular Sequence Data ; Nuclear Proteins/chemistry/*metabolism ; Nucleosomes/chemistry/metabolism ; Phosphoproteins/chemistry/*metabolism ; Protein Binding ; Protein Conformation ; Substrate Specificity
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  • 19
    Publication Date: 2014-11-11
    Description: The TMEM16 family of proteins, also known as anoctamins, features a remarkable functional diversity. This family contains the long sought-after Ca(2+)-activated chloride channels as well as lipid scramblases and cation channels. Here we present the crystal structure of a TMEM16 family member from the fungus Nectria haematococca that operates as a Ca(2+)-activated lipid scramblase. Each subunit of the homodimeric protein contains ten transmembrane helices and a hydrophilic membrane-traversing cavity that is exposed to the lipid bilayer as a potential site of catalysis. This cavity harbours a conserved Ca(2+)-binding site located within the hydrophobic core of the membrane. Mutations of residues involved in Ca(2+) coordination affect both lipid scrambling in N. haematococca TMEM16 and ion conduction in the Cl(-) channel TMEM16A. The structure reveals the general architecture of the family and its mode of Ca(2+) activation. It also provides insight into potential scrambling mechanisms and serves as a framework to unravel the conduction of ions in certain TMEM16 proteins.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brunner, Janine D -- Lim, Novandy K -- Schenck, Stephan -- Duerst, Alessia -- Dutzler, Raimund -- England -- Nature. 2014 Dec 11;516(7530):207-12. doi: 10.1038/nature13984. Epub 2014 Nov 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383531" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Binding Sites/genetics ; Calcium/chemistry/*metabolism/pharmacology ; Chloride Channels/*chemistry/genetics/*metabolism ; Crystallography, X-Ray ; Electric Conductivity ; Humans ; Hydrophobic and Hydrophilic Interactions ; Ion Transport/drug effects ; Lipid Bilayers/chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Nectria/*chemistry/enzymology/genetics ; Neoplasm Proteins/chemistry ; Phospholipid Transfer Proteins/*chemistry/genetics/*metabolism ; Protein Multimerization ; Protein Structure, Secondary ; Protein Subunits/chemistry/metabolism
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  • 20
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    Nature Publishing Group (NPG)
    Publication Date: 2014-04-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boone, David -- England -- Nature. 2014 Apr 10;508(7495):186. doi: 10.1038/508186e.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Indiana University School of Medicine - South Bend, Indiana, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24717504" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Catalytic Domain ; Humans ; Skin Neoplasms/genetics ; Tumor Suppressor Proteins/*chemistry/genetics
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  • 21
    Publication Date: 2014-05-09
    Description: Efficient duplication of the genome requires the concerted action of helicase and DNA polymerases at replication forks to avoid stalling of the replication machinery and consequent genomic instability. In eukaryotes, the physical coupling between helicase and DNA polymerases remains poorly understood. Here we define the molecular mechanism by which the yeast Ctf4 protein links the Cdc45-MCM-GINS (CMG) DNA helicase to DNA polymerase alpha (Pol alpha) within the replisome. We use X-ray crystallography and electron microscopy to show that Ctf4 self-associates in a constitutive disk-shaped trimer. Trimerization depends on a beta-propeller domain in the carboxy-terminal half of the protein, which is fused to a helical extension that protrudes from one face of the trimeric disk. Critically, Pol alpha and the CMG helicase share a common mechanism of interaction with Ctf4. We show that the amino-terminal tails of the catalytic subunit of Pol alpha and the Sld5 subunit of GINS contain a conserved Ctf4-binding motif that docks onto the exposed helical extension of a Ctf4 protomer within the trimer. Accordingly, we demonstrate that one Ctf4 trimer can support binding of up to three partner proteins, including the simultaneous association with both Pol alpha and GINS. Our findings indicate that Ctf4 can couple two molecules of Pol alpha to one CMG helicase within the replisome, providing a new model for lagging-strand synthesis in eukaryotes that resembles the emerging model for the simpler replisome of Escherichia coli. The ability of Ctf4 to act as a platform for multivalent interactions illustrates a mechanism for the concurrent recruitment of factors that act together at the fork.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059944/" 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/PMC4059944/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Simon, Aline C -- Zhou, Jin C -- Perera, Rajika L -- van Deursen, Frederick -- Evrin, Cecile -- Ivanova, Marina E -- Kilkenny, Mairi L -- Renault, Ludovic -- Kjaer, Svend -- Matak-Vinkovic, Dijana -- Labib, Karim -- Costa, Alessandro -- Pellegrini, Luca -- 084279/Wellcome Trust/United Kingdom -- Wellcome Trust/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2014 Jun 12;510(7504):293-7. doi: 10.1038/nature13234. Epub 2014 May 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK [2]. ; 1] Clare Hall Laboratories, Cancer Research UK London Research Institute, London EN6 3LD, UK [2]. ; 1] Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK [2] Imperial College, South Kensington, London SW7 2AZ, UK (R.L.P.); Cancer Research UK London Research Institute, London WC2A 3LY, UK (M.E.I.). ; Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK. ; MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK. ; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK. ; Clare Hall Laboratories, Cancer Research UK London Research Institute, London EN6 3LD, UK. ; Protein purification, Cancer Research UK London Research Institute, London WC2A 3LY, UK. ; Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24805245" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Catalytic Domain ; Conserved Sequence ; Crystallography, X-Ray ; DNA Helicases/chemistry/*metabolism/ultrastructure ; DNA Polymerase I/chemistry/*metabolism/ultrastructure ; *DNA Replication ; DNA-Binding Proteins/*chemistry/*metabolism/ultrastructure ; DNA-Directed DNA Polymerase/*chemistry/*metabolism ; Microscopy, Electron ; Minichromosome Maintenance Proteins/chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Multienzyme Complexes/*chemistry/*metabolism ; Nuclear Proteins/chemistry/metabolism ; Protein Binding ; *Protein Multimerization ; Protein Structure, Quaternary ; Protein Subunits/chemistry/metabolism ; Saccharomyces cerevisiae/*chemistry/ultrastructure ; Saccharomyces cerevisiae Proteins/*chemistry/*metabolism/ultrastructure
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  • 22
    Publication Date: 2014-03-05
    Description: Recognition of modified histones by 'reader' proteins plays a critical role in the regulation of chromatin. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions after RNA polymerase II elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin to a relatively repressive state, thus suppressing cryptic transcription. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is further complicated by the transcription-coupled incorporation of the histone variant H3.3 in gene bodies. Here we show that the candidate tumour suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates RNA polymerase II elongation. Structural studies show that in addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific 'Ser 31' residue in a composite pocket formed by the tandem bromo-PWWP domains of ZMYND11. Chromatin immunoprecipitation followed by sequencing shows a genome-wide co-localization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription co-repressor by modulating RNA polymerase II at the elongation stage. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumour cell growth; low expression levels of ZMYND11 in breast cancer patients correlate with worse prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth in vitro and tumour formation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 that links the histone-variant-mediated transcription elongation control to tumour suppression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142212/" 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/PMC4142212/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wen, Hong -- Li, Yuanyuan -- Xi, Yuanxin -- Jiang, Shiming -- Stratton, Sabrina -- Peng, Danni -- Tanaka, Kaori -- Ren, Yongfeng -- Xia, Zheng -- Wu, Jun -- Li, Bing -- Barton, Michelle C -- Li, Wei -- Li, Haitao -- Shi, Xiaobing -- CA016672/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- R01 GM090077/GM/NIGMS NIH HHS/ -- R01 HG007538/HG/NHGRI NIH HHS/ -- R01GM090077/GM/NIGMS NIH HHS/ -- R01HG007538/HG/NHGRI NIH HHS/ -- England -- Nature. 2014 Apr 10;508(7495):263-8. doi: 10.1038/nature13045. Epub 2014 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for Cancer Epigenetics, Center for Genetics and Genomics, and Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3]. ; 1] MOE Key Laboratory of Protein Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China [2] Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China [3]. ; 1] Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2]. ; Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] MOE Key Laboratory of Protein Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China [2] Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. ; Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for Cancer Epigenetics, Center for Genetics and Genomics, and Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3] Genes and Development Graduate Program, The University of Texas Graduate School of Biomedical Sciences, Houston, Teaxs 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24590075" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Breast Neoplasms/*genetics/metabolism/*pathology ; Carrier Proteins/chemistry/*metabolism ; Chromatin/genetics/metabolism ; Co-Repressor Proteins/chemistry/metabolism ; Crystallography, X-Ray ; Disease-Free Survival ; Female ; Gene Expression Regulation, Neoplastic/genetics ; Histones/chemistry/*metabolism ; Humans ; Lysine/*metabolism ; Methylation ; Mice ; Mice, Nude ; Models, Molecular ; Molecular Sequence Data ; Oncogenes/genetics ; Prognosis ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary ; RNA Polymerase II/*metabolism ; Substrate Specificity ; *Transcription Elongation, Genetic
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  • 23
    Publication Date: 2014-08-30
    Description: Without an approved vaccine or treatments, Ebola outbreak management has been limited to palliative care and barrier methods to prevent transmission. These approaches, however, have yet to end the 2014 outbreak of Ebola after its prolonged presence in West Africa. Here we show that a combination of monoclonal antibodies (ZMapp), optimized from two previous antibody cocktails, is able to rescue 100% of rhesus macaques when treatment is initiated up to 5 days post-challenge. High fever, viraemia and abnormalities in blood count and blood chemistry were evident in many animals before ZMapp intervention. Advanced disease, as indicated by elevated liver enzymes, mucosal haemorrhages and generalized petechia could be reversed, leading to full recovery. ELISA and neutralizing antibody assays indicate that ZMapp is cross-reactive with the Guinean variant of Ebola. ZMapp exceeds the efficacy of any other therapeutics described so far, and results warrant further development of this cocktail for clinical use.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214273/" 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/PMC4214273/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qiu, Xiangguo -- Wong, Gary -- Audet, Jonathan -- Bello, Alexander -- Fernando, Lisa -- Alimonti, Judie B -- Fausther-Bovendo, Hugues -- Wei, Haiyan -- Aviles, Jenna -- Hiatt, Ernie -- Johnson, Ashley -- Morton, Josh -- Swope, Kelsi -- Bohorov, Ognian -- Bohorova, Natasha -- Goodman, Charles -- Kim, Do -- Pauly, Michael H -- Velasco, Jesus -- Pettitt, James -- Olinger, Gene G -- Whaley, Kevin -- Xu, Bianli -- Strong, James E -- Zeitlin, Larry -- Kobinger, Gary P -- U19 AI109762/AI/NIAID NIH HHS/ -- U19AI109762/AI/NIAID NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2014 Oct 2;514(7520):47-53. doi: 10.1038/nature13777. Epub 2014 Aug 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Laboratory for Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada. ; 1] National Laboratory for Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada [2] Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada. ; 1] National Laboratory for Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada [2] Institute of Infectious Disease, Henan Centre for Disease Control and Prevention, Zhengzhou, 450012 Henan, China. ; Kentucky BioProcessing, Owensboro, Kentucky 42301, USA. ; Mapp Biopharmaceutical Inc., San Diego, California 92121, USA. ; 1] United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Frederick, Maryland 21702, USA [2] Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland 21702, USA. ; Institute of Infectious Disease, Henan Centre for Disease Control and Prevention, Zhengzhou, 450012 Henan, China. ; 1] National Laboratory for Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada [2] Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada [3] Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba R3A 1S1, Canada. ; 1] National Laboratory for Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada [2] Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada [3] Department of Immunology, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada [4] Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25171469" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Antibodies, Monoclonal/immunology/*therapeutic use ; Antibodies, Neutralizing/immunology/therapeutic use ; Antibodies, Viral/immunology/*therapeutic use ; Cross Reactions/immunology ; Ebolavirus/immunology ; Enzyme-Linked Immunosorbent Assay ; Female ; Guinea ; Guinea Pigs ; Hemorrhagic Fever, Ebola/blood/*drug therapy/immunology/virology ; *Immunization, Passive ; Macaca mulatta/immunology/virology ; Male ; Molecular Sequence Data ; Sequence Alignment ; Viral Envelope Proteins/chemistry/immunology ; Viremia/drug therapy/immunology/virology
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  • 24
    Publication Date: 2014-11-05
    Description: The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) 〈 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR 〈 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402723/" 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/PMC4402723/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉De Rubeis, Silvia -- He, Xin -- Goldberg, Arthur P -- Poultney, Christopher S -- Samocha, Kaitlin -- Cicek, A Erucment -- Kou, Yan -- Liu, Li -- Fromer, Menachem -- Walker, Susan -- Singh, Tarinder -- Klei, Lambertus -- Kosmicki, Jack -- Shih-Chen, Fu -- Aleksic, Branko -- Biscaldi, Monica -- Bolton, Patrick F -- Brownfeld, Jessica M -- Cai, Jinlu -- Campbell, Nicholas G -- Carracedo, Angel -- Chahrour, Maria H -- Chiocchetti, Andreas G -- Coon, Hilary -- Crawford, Emily L -- Curran, Sarah R -- Dawson, Geraldine -- Duketis, Eftichia -- Fernandez, Bridget A -- Gallagher, Louise -- Geller, Evan -- Guter, Stephen J -- Hill, R Sean -- Ionita-Laza, Juliana -- Jimenz Gonzalez, Patricia -- Kilpinen, Helena -- Klauck, Sabine M -- Kolevzon, Alexander -- Lee, Irene -- Lei, Irene -- Lei, Jing -- Lehtimaki, Terho -- Lin, Chiao-Feng -- Ma'ayan, Avi -- Marshall, Christian R -- McInnes, Alison L -- Neale, Benjamin -- Owen, Michael J -- Ozaki, Noriio -- Parellada, Mara -- Parr, Jeremy R -- Purcell, Shaun -- Puura, Kaija -- Rajagopalan, Deepthi -- Rehnstrom, Karola -- Reichenberg, Abraham -- Sabo, Aniko -- Sachse, Michael -- Sanders, Stephan J -- Schafer, Chad -- Schulte-Ruther, Martin -- Skuse, David -- Stevens, Christine -- Szatmari, Peter -- Tammimies, Kristiina -- Valladares, Otto -- Voran, Annette -- Li-San, Wang -- Weiss, Lauren A -- Willsey, A Jeremy -- Yu, Timothy W -- Yuen, Ryan K C -- DDD Study -- Homozygosity Mapping Collaborative for Autism -- UK10K Consortium -- Cook, Edwin H -- Freitag, Christine M -- Gill, Michael -- Hultman, Christina M -- Lehner, Thomas -- Palotie, Aaarno -- Schellenberg, Gerard D -- Sklar, Pamela -- State, Matthew W -- Sutcliffe, James S -- Walsh, Christiopher A -- Scherer, Stephen W -- Zwick, Michael E -- Barett, Jeffrey C -- Cutler, David J -- Roeder, Kathryn -- Devlin, Bernie -- Daly, Mark J -- Buxbaum, Joseph D -- 5UL1 RR024975/RR/NCRR NIH HHS/ -- MH077139/MH/NIMH NIH HHS/ -- MH089482/MH/NIMH NIH HHS/ -- MH095034/MH/NIMH NIH HHS/ -- P30 HD15052/HD/NICHD NIH HHS/ -- P50 HD055751/HD/NICHD NIH HHS/ -- R01 MH061009/MH/NIMH NIH HHS/ -- R01 MH083565/MH/NIMH NIH HHS/ -- R01 MH089482/MH/NIMH NIH HHS/ -- R01 MH094400/MH/NIMH NIH HHS/ -- R01 MH095797/MH/NIMH NIH HHS/ -- R01 MH097849/MH/NIMH NIH HHS/ -- R01 MH100229/MH/NIMH NIH HHS/ -- R01 NS073601/NS/NINDS NIH HHS/ -- R01MH083565/MH/NIMH NIH HHS/ -- R01MH089208/MH/NIMH NIH HHS/ -- R37 MH057881/MH/NIMH NIH HHS/ -- RC2MH089952/MH/NIMH NIH HHS/ -- T32 HG002295/HG/NHGRI NIH HHS/ -- U01 MH100209/MH/NIMH NIH HHS/ -- U01 MH100229/MH/NIMH NIH HHS/ -- U01 MH100233/MH/NIMH NIH HHS/ -- U01 MH100239/MH/NIMH NIH HHS/ -- U01MH100209/MH/NIMH NIH HHS/ -- U01MH100229/MH/NIMH NIH HHS/ -- U01MH100233/MH/NIMH NIH HHS/ -- U01MH100239/MH/NIMH NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- UL1TR000445/TR/NCATS NIH HHS/ -- WT091310/Wellcome Trust/United Kingdom -- WT098051/Wellcome Trust/United Kingdom -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Nov 13;515(7526):209-15. doi: 10.1038/nature13772. Epub 2014 Oct 29.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363760" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Child Development Disorders, Pervasive/*genetics/pathology ; Chromatin/*genetics/metabolism ; Chromatin Assembly and Disassembly ; Exome/genetics ; Female ; Genetic Predisposition to Disease/*genetics ; Germ-Line Mutation/genetics ; Humans ; Male ; Molecular Sequence Data ; Mutation/*genetics ; Mutation, Missense/genetics ; Nerve Net/metabolism ; Odds Ratio ; Synapses/*metabolism ; Transcription, Genetic/*genetics
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  • 25
    Publication Date: 2014-01-10
    Description: The human immunodeficiency virus (HIV)-1 protein Vif has a central role in the neutralization of host innate defences by hijacking cellular proteasomal degradation pathways to subvert the antiviral activity of host restriction factors; however, the underlying mechanism by which Vif achieves this remains unclear. Here we report a crystal structure of the Vif-CBF-beta-CUL5-ELOB-ELOC complex. The structure reveals that Vif, by means of two domains, organizes formation of the pentameric complex by interacting with CBF-beta, CUL5 and ELOC. The larger domain (alpha/beta domain) of Vif binds to the same side of CBF-beta as RUNX1, indicating that Vif and RUNX1 are exclusive for CBF-beta binding. Interactions of the smaller domain (alpha-domain) of Vif with ELOC and CUL5 are cooperative and mimic those of SOCS2 with the latter two proteins. A unique zinc-finger motif of Vif, which is located between the two Vif domains, makes no contacts with the other proteins but stabilizes the conformation of the alpha-domain, which may be important for Vif-CUL5 interaction. Together, our data reveal the structural basis for Vif hijacking of the CBF-beta and CUL5 E3 ligase complex, laying a foundation for rational design of novel anti-HIV drugs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guo, Yingying -- Dong, Liyong -- Qiu, Xiaolin -- Wang, Yishu -- Zhang, Bailing -- Liu, Hongnan -- Yu, You -- Zang, Yi -- Yang, Maojun -- Huang, Zhiwei -- England -- Nature. 2014 Jan 9;505(7482):229-33. doi: 10.1038/nature12884.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China [2]. ; School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China. ; MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, 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/24402281" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Core Binding Factor Alpha 2 Subunit/metabolism ; Core Binding Factor beta Subunit/*chemistry/*metabolism ; Crystallography, X-Ray ; Cullin Proteins/*chemistry/*metabolism ; Humans ; Models, Molecular ; Molecular Sequence Data ; Multiprotein Complexes/chemistry/metabolism ; Protein Binding ; Protein Stability ; Protein Structure, Tertiary ; Suppressor of Cytokine Signaling Proteins ; Transcription Factors/chemistry/metabolism ; vif Gene Products, Human Immunodeficiency Virus/*chemistry/*metabolism
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  • 26
    Publication Date: 2014-05-13
    Description: 2-Oxoglutarate (2OG)-dependent oxygenases have important roles in the regulation of gene expression via demethylation of N-methylated chromatin components and in the hydroxylation of transcription factors and splicing factor proteins. Recently, 2OG-dependent oxygenases that catalyse hydroxylation of transfer RNA and ribosomal proteins have been shown to be important in translation relating to cellular growth, TH17-cell differentiation and translational accuracy. The finding that ribosomal oxygenases (ROXs) occur in organisms ranging from prokaryotes to humans raises questions as to their structural and evolutionary relationships. In Escherichia coli, YcfD catalyses arginine hydroxylation in the ribosomal protein L16; in humans, MYC-induced nuclear antigen (MINA53; also known as MINA) and nucleolar protein 66 (NO66) catalyse histidine hydroxylation in the ribosomal proteins RPL27A and RPL8, respectively. The functional assignments of ROXs open therapeutic possibilities via either ROX inhibition or targeting of differentially modified ribosomes. Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. Comparison of ROX crystal structures with those of other JmjC-domain-containing hydroxylases, including the hypoxia-inducible factor asparaginyl hydroxylase FIH and histone N(epsilon)-methyl lysine demethylases, identifies branch points in 2OG-dependent oxygenase evolution and distinguishes between JmjC-containing hydroxylases and demethylases catalysing modifications of translational and transcriptional machinery. The structures reveal that new protein hydroxylation activities can evolve by changing the coordination position from which the iron-bound substrate-oxidizing species reacts. This coordination flexibility has probably contributed to the evolution of the wide range of reactions catalysed by oxygenases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066111/" 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/PMC4066111/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chowdhury, Rasheduzzaman -- Sekirnik, Rok -- Brissett, Nigel C -- Krojer, Tobias -- Ho, Chia-Hua -- Ng, Stanley S -- Clifton, Ian J -- Ge, Wei -- Kershaw, Nadia J -- Fox, Gavin C -- Muniz, Joao R C -- Vollmar, Melanie -- Phillips, Claire -- Pilka, Ewa S -- Kavanagh, Kathryn L -- von Delft, Frank -- Oppermann, Udo -- McDonough, Michael A -- Doherty, Aidan J -- Schofield, Christopher J -- 092809/Wellcome Trust/United Kingdom -- 6947/Cancer Research UK/United Kingdom -- BB/C518230/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/L009846/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- Arthritis Research UK/United Kingdom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2014 Jun 19;510(7505):422-6. doi: 10.1038/nature13263. Epub 2014 May 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Department of Chemistry and Oxford Centre for Integrative Systems Biology, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK. ; 1] The Department of Chemistry and Oxford Centre for Integrative Systems Biology, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK [2]. ; 1] Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK [2]. ; Structural Genomics Consortium, University of Oxford, Headington, Oxford OX3 7DQ, UK. ; Synchrotron SOLEIL, Saint Aubin, 91192 Gif-sur-Yvette Cedex, France. ; 1] Structural Genomics Consortium, University of Oxford, Headington, Oxford OX3 7DQ, UK [2] NIHR Oxford Biomedical Research Unit, Botnar Research Centre, Oxford OX3 7LD, UK. ; Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24814345" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Catalytic Domain ; Conserved Sequence ; Eukaryota/classification/*enzymology ; Humans ; *Models, Molecular ; Oxygenases/*chemistry/metabolism ; Phylogeny ; Prokaryotic Cells/classification/*enzymology ; Protein Folding ; Protein Structure, Tertiary ; Ribosomes/*enzymology ; Sequence Alignment
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  • 27
    Publication Date: 2014-07-22
    Description: Programmed -1 ribosomal frameshift (-1 PRF) signals redirect translating ribosomes to slip back one base on messenger RNAs. Although well characterized in viruses, how these elements may regulate cellular gene expression is not understood. Here we describe a -1 PRF signal in the human mRNA encoding CCR5, the HIV-1 co-receptor. CCR5 mRNA-mediated -1 PRF is directed by an mRNA pseudoknot, and is stimulated by at least two microRNAs. Mapping the mRNA-miRNA interaction suggests that formation of a triplex RNA structure stimulates -1 PRF. A -1 PRF event on the CCR5 mRNA directs translating ribosomes to a premature termination codon, destabilizing it through the nonsense-mediated mRNA decay pathway. At least one additional mRNA decay pathway is also involved. Functional -1 PRF signals that seem to be regulated by miRNAs are also demonstrated in mRNAs encoding six other cytokine receptors, suggesting a novel mode through which immune responses may be fine-tuned in mammalian cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369343/" 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/PMC4369343/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Belew, Ashton Trey -- Meskauskas, Arturas -- Musalgaonkar, Sharmishtha -- Advani, Vivek M -- Sulima, Sergey O -- Kasprzak, Wojciech K -- Shapiro, Bruce A -- Dinman, Jonathan D -- 5 R01GM058859/GM/NIGMS NIH HHS/ -- HHSN261200800001/PHS HHS/ -- R01 GM058859/GM/NIGMS NIH HHS/ -- R01 HL119439/HL/NHLBI NIH HHS/ -- R21 GM068123/GM/NIGMS NIH HHS/ -- R21GM068123/GM/NIGMS NIH HHS/ -- T32 AI051967/AI/NIAID NIH HHS/ -- T32AI051967/AI/NIAID NIH HHS/ -- T32GM080201/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2014 Aug 21;512(7514):265-9. doi: 10.1038/nature13429. Epub 2014 Jul 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA [2]. ; 1] Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA [2] Department of Biotechnology and Microbiology, Vilnius University, Vilnius, LT 03101, Lithuania [3]. ; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA. ; 1] Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA [2] VIB Center for the Biology of Disease, KU Leuven, Campus Gasthuisberg, Herestraat 49, bus 602, 3000 Leuven, Belgium. ; Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA. ; Basic Research Laboratory, National Cancer Institute, Frederick, Maryland 21702, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043019" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Base Sequence ; Binding Sites ; Cell Survival ; Codon, Nonsense/genetics ; Frameshifting, Ribosomal/*genetics ; HeLa Cells ; Humans ; MicroRNAs/*genetics ; Models, Molecular ; Molecular Sequence Data ; *Nonsense Mediated mRNA Decay ; Nucleic Acid Conformation ; RNA, Messenger/chemistry/*genetics/*metabolism ; Receptors, CCR5/*genetics ; Receptors, Interleukin/genetics ; Regulatory Sequences, Ribonucleic Acid ; Ribosomes/metabolism
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  • 28
    Publication Date: 2014-01-28
    Description: A well-balanced human diet includes a significant intake of non-starch polysaccharides, collectively termed 'dietary fibre', from the cell walls of diverse fruits and vegetables. Owing to the paucity of alimentary enzymes encoded by the human genome, our ability to derive energy from dietary fibre depends on the saccharification and fermentation of complex carbohydrates by the massive microbial community residing in our distal gut. The xyloglucans (XyGs) are a ubiquitous family of highly branched plant cell wall polysaccharides whose mechanism(s) of degradation in the human gut and consequent importance in nutrition have been unclear. Here we demonstrate that a single, complex gene locus in Bacteroides ovatus confers XyG catabolism in this common colonic symbiont. Through targeted gene disruption, biochemical analysis of all predicted glycoside hydrolases and carbohydrate-binding proteins, and three-dimensional structural determination of the vanguard endo-xyloglucanase, we reveal the molecular mechanisms through which XyGs are hydrolysed to component monosaccharides for further metabolism. We also observe that orthologous XyG utilization loci (XyGULs) serve as genetic markers of XyG catabolism in Bacteroidetes, that XyGULs are restricted to a limited number of phylogenetically diverse strains, and that XyGULs are ubiquitous in surveyed human metagenomes. Our findings reveal that the metabolism of even highly abundant components of dietary fibre may be mediated by niche species, which has immediate fundamental and practical implications for gut symbiont population ecology in the context of human diet, nutrition and health.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282169/" 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/PMC4282169/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Larsbrink, Johan -- Rogers, Theresa E -- Hemsworth, Glyn R -- McKee, Lauren S -- Tauzin, Alexandra S -- Spadiut, Oliver -- Klinter, Stefan -- Pudlo, Nicholas A -- Urs, Karthik -- Koropatkin, Nicole M -- Creagh, A Louise -- Haynes, Charles A -- Kelly, Amelia G -- Cederholm, Stefan Nilsson -- Davies, Gideon J -- Martens, Eric C -- Brumer, Harry -- BB/I014802/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- DK084214/DK/NIDDK NIH HHS/ -- GM099513/GM/NIGMS NIH HHS/ -- K01 DK084214/DK/NIDDK NIH HHS/ -- R01 GM099513/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Feb 27;506(7489):498-502. doi: 10.1038/nature12907. Epub 2014 Jan 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Glycoscience, School of Biotechnology, Royal Institute of Technology (KTH), AlbaNova University Centre, 106 91 Stockholm, Sweden [2]. ; 1] Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2]. ; 1] Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD, UK [2]. ; 1] Division of Glycoscience, School of Biotechnology, Royal Institute of Technology (KTH), AlbaNova University Centre, 106 91 Stockholm, Sweden [2] Wallenberg Wood Science Center, Royal Institute of Technology (KTH), Teknikringen 56-58, 100 44 Stockholm, Sweden. ; Michael Smith Laboratories and Department of Chemistry, University of British Columbia, 2185 East Mall, Vancouver, British Columbia V6T 1Z4, Canada. ; Division of Glycoscience, School of Biotechnology, Royal Institute of Technology (KTH), AlbaNova University Centre, 106 91 Stockholm, Sweden. ; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; Michael Smith Laboratories and Department of Chemical and Biological Engineering, University of British Columbia, 2185 East Mall, Vancouver, British Columbia V6T 1Z4, Canada. ; Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD, UK. ; 1] Division of Glycoscience, School of Biotechnology, Royal Institute of Technology (KTH), AlbaNova University Centre, 106 91 Stockholm, Sweden [2] Michael Smith Laboratories and Department of Chemistry, University of British Columbia, 2185 East Mall, Vancouver, British Columbia V6T 1Z4, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24463512" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Bacteroides/enzymology/*genetics/growth & development/*metabolism ; Carbohydrate Metabolism/genetics ; Carbohydrate Sequence ; Cell Wall/chemistry ; Crystallography, X-Ray ; Diet ; Dietary Fiber ; Evolution, Molecular ; Gastrointestinal Tract/*microbiology ; Genetic Loci/*genetics ; Glucans/chemistry/*metabolism ; Glycoside Hydrolases/chemistry/genetics/metabolism ; Humans ; Metagenome ; Models, Molecular ; Molecular Sequence Data ; Phylogeny ; Protein Structure, Tertiary ; Symbiosis ; Xylans/chemistry/*metabolism
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  • 29
    Publication Date: 2014-01-07
    Description: Cytosine residues in mammalian DNA occur in five forms: cytosine (C), 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). The ten-eleven translocation (Tet) dioxygenases convert 5mC to 5hmC, 5fC and 5caC in three consecutive, Fe(II)- and alpha-ketoglutarate-dependent oxidation reactions. The Tet family of dioxygenases is widely distributed across the tree of life, including in the heterolobosean amoeboflagellate Naegleria gruberi. The genome of Naegleria encodes homologues of mammalian DNA methyltransferase and Tet proteins. Here we study biochemically and structurally one of the Naegleria Tet-like proteins (NgTet1), which shares significant sequence conservation (approximately 14% identity or 39% similarity) with mammalian Tet1. Like mammalian Tet proteins, NgTet1 acts on 5mC and generates 5hmC, 5fC and 5caC. The crystal structure of NgTet1 in complex with DNA containing a 5mCpG site revealed that NgTet1 uses a base-flipping mechanism to access 5mC. The DNA is contacted from the minor groove and bent towards the major groove. The flipped 5mC is positioned in the active-site pocket with planar stacking contacts, Watson-Crick polar hydrogen bonds and van der Waals interactions specific for 5mC. The sequence conservation between NgTet1 and mammalian Tet1, including residues involved in structural integrity and functional significance, suggests structural conservation across phyla.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364404/" 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/PMC4364404/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hashimoto, Hideharu -- Pais, June E -- Zhang, Xing -- Saleh, Lana -- Fu, Zheng-Qing -- Dai, Nan -- Correa, Ivan R Jr -- Zheng, Yu -- Cheng, Xiaodong -- GM049245/GM/NIGMS NIH HHS/ -- GM095209/GM/NIGMS NIH HHS/ -- GM105132/GM/NIGMS NIH HHS/ -- R01 GM049245/GM/NIGMS NIH HHS/ -- R44 GM105132/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Feb 20;506(7488):391-5. doi: 10.1038/nature12905. Epub 2013 Dec 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, Georgia 30322, USA. ; New England Biolabs, 240 County Road, Ipswich, Massachusetts 01938, USA. ; 1] Department of Biochemistry & Molecular Biology, University of Georgia, Athens, Georgia 30602, USA [2] Sector 22, Advanced Photon Source, Argonne National Laboratory, Argonne, Illinois 60439, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24390346" target="_blank"〉PubMed〈/a〉
    Keywords: 5-Methylcytosine/chemistry/*metabolism ; Amino Acid Sequence ; Animals ; Catalytic Domain/genetics ; Conserved Sequence ; Crystallography, X-Ray ; Cytosine/analogs & derivatives/metabolism ; DNA/*chemistry/*metabolism ; DNA-Binding Proteins/chemistry/genetics/metabolism ; Dioxygenases/*chemistry/*metabolism ; Escherichia coli Proteins/chemistry ; HEK293 Cells ; Humans ; Hydrogen Bonding ; Mice ; Mixed Function Oxygenases/chemistry ; Models, Molecular ; Molecular Sequence Data ; Naegleria/*enzymology/genetics ; Proto-Oncogene Proteins/chemistry/genetics/metabolism ; Structural Homology, Protein ; Structure-Activity Relationship ; Substrate Specificity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
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  • 30
    Publication Date: 2014-09-26
    Description: Post-translational histone modifications have a critical role in regulating transcription, the cell cycle, DNA replication and DNA damage repair. The identification of new histone modifications critical for transcriptional regulation at initiation, elongation or termination is of particular interest. Here we report a new layer of regulation in transcriptional elongation that is conserved from yeast to mammals. This regulation is based on the phosphorylation of a highly conserved tyrosine residue, Tyr 57, in histone H2A and is mediated by the unsuspected tyrosine kinase activity of casein kinase 2 (CK2). Mutation of Tyr 57 in H2A in yeast or inhibition of CK2 activity impairs transcriptional elongation in yeast as well as in mammalian cells. Genome-wide binding analysis reveals that CK2alpha, the catalytic subunit of CK2, binds across RNA-polymerase-II-transcribed coding genes and active enhancers. Mutation of Tyr 57 causes a loss of H2B mono-ubiquitination as well as H3K4me3 and H3K79me3, histone marks associated with active transcription. Mechanistically, both CK2 inhibition and the H2A(Y57F) mutation enhance H2B deubiquitination activity of the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex, suggesting a critical role of this phosphorylation in coordinating the activity of the SAGA complex during transcription. Together, these results identify a new component of regulation in transcriptional elongation based on CK2-dependent tyrosine phosphorylation of the globular domain of H2A.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461219/" 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/PMC4461219/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Basnet, Harihar -- Su, Xue B -- Tan, Yuliang -- Meisenhelder, Jill -- Merkurjev, Daria -- Ohgi, Kenneth A -- Hunter, Tony -- Pillus, Lorraine -- Rosenfeld, Michael G -- CA173903/CA/NCI NIH HHS/ -- CA82683/CA/NCI NIH HHS/ -- DK018477/DK/NIDDK NIH HHS/ -- DK039949/DK/NIDDK NIH HHS/ -- GM033279/GM/NIGMS NIH HHS/ -- HL065445/HL/NHLBI NIH HHS/ -- NS034934/NS/NINDS NIH HHS/ -- P30 CA023100/CA/NCI NIH HHS/ -- R01 DK018477/DK/NIDDK NIH HHS/ -- R01 GM033279/GM/NIGMS NIH HHS/ -- R01 HL065445/HL/NHLBI NIH HHS/ -- R01 NS034934/NS/NINDS NIH HHS/ -- R37 DK039949/DK/NIDDK NIH HHS/ -- T32 DK007541/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Dec 11;516(7530):267-71. doi: 10.1038/nature13736. Epub 2014 Sep 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Howard Hughes Medical Institute, Department of Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Biomedical Sciences Graduate Program, School of Medicine, University of California San Diego, La Jolla, California 92093, USA. ; Division of Biological Sciences, Section of Molecular Biology, UCSD Moores Cancer Center, University of California San Diego, La Jolla, California 92093-0347, USA. ; Howard Hughes Medical Institute, Department of Medicine, University of California San Diego, La Jolla, California 92093, USA. ; Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; 1] Howard Hughes Medical Institute, Department of Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Bioinformatics and Systems Biology Program, Department of Bioengineering, University of California San Diego, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25252977" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Casein Kinase II/*metabolism ; Cell Line ; Conserved Sequence ; Histones/*chemistry/genetics/*metabolism ; Humans ; Molecular Sequence Data ; Phosphorylation ; Saccharomyces cerevisiae/genetics/metabolism ; *Transcription Elongation, Genetic ; Tyrosine/chemistry/*metabolism ; Ubiquitination/genetics
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  • 31
    Publication Date: 2014-03-22
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cappellini, Enrico -- Collins, Matthew J -- Gilbert, M Thomas P -- New York, N.Y. -- Science. 2014 Mar 21;343(6177):1320-2. doi: 10.1126/science.1249274.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24653025" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Databases, Protein ; Fossils ; Humans ; *Mass Spectrometry/instrumentation/methods ; Mummies ; Proteins/*chemistry/isolation & purification ; Proteolysis ; Proteomics
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  • 32
    Publication Date: 2014-11-22
    Description: Chromosome segregation depends on sister chromatid cohesion mediated by cohesin. The cohesin subunits Smc1, Smc3, and Scc1 form tripartite rings that are thought to open at distinct sites to allow entry and exit of DNA. However, direct evidence for the existence of open forms of cohesin is lacking. We found that cohesin's proposed DNA exit gate is formed by interactions between Scc1 and the coiled-coil region of Smc3. Mutation of this interface abolished cohesin's ability to stably associate with chromatin and to mediate cohesion. Electron microscopy revealed that weakening of the Smc3-Scc1 interface resulted in opening of cohesin rings, as did proteolytic cleavage of Scc1. These open forms may resemble intermediate states of cohesin normally generated by the release factor Wapl and the protease separase, respectively.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huis in 't Veld, Pim J -- Herzog, Franz -- Ladurner, Rene -- Davidson, Iain F -- Piric, Sabina -- Kreidl, Emanuel -- Bhaskara, Venugopal -- Aebersold, Ruedi -- Peters, Jan-Michael -- New York, N.Y. -- Science. 2014 Nov 21;346(6212):968-72. doi: 10.1126/science.1256904.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), 1030 Vienna, Austria. ; Department of Biology, Institute of Molecular Systems Biology, Eidgenossische Technische Hochschule (ETH) Zurich, 8093 Zurich, Switzerland. Department of Biochemistry, Gene Center, Ludwig-Maximilian University, 81377 Munich, Germany. ; Department of Biology, Institute of Molecular Systems Biology, Eidgenossische Technische Hochschule (ETH) Zurich, 8093 Zurich, Switzerland. ; Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), 1030 Vienna, Austria. peters@imp.ac.at.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25414306" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Carrier Proteins/genetics/metabolism ; Cell Cycle Proteins/chemistry/genetics/*metabolism ; Chondroitin Sulfate Proteoglycans/chemistry/genetics/*metabolism ; Chromatin/metabolism ; Chromosomal Proteins, Non-Histone/chemistry/genetics/*metabolism ; *Chromosome Segregation ; DNA/*metabolism ; DNA Replication ; Humans ; Mass Spectrometry ; Microscopy, Electron ; Molecular Sequence Data ; Nuclear Proteins/chemistry/genetics/*metabolism ; Phosphoproteins/chemistry/genetics/*metabolism ; Protein Multimerization ; Protein Structure, Tertiary ; Proto-Oncogene Proteins/genetics/metabolism ; Separase/metabolism
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  • 33
    Publication Date: 2014-05-31
    Description: Phosphatidylinositol 4-kinases (PI4Ks) and small guanosine triphosphatases (GTPases) are essential for processes that require expansion and remodeling of phosphatidylinositol 4-phosphate (PI4P)-containing membranes, including cytokinesis, intracellular development of malarial pathogens, and replication of a wide range of RNA viruses. However, the structural basis for coordination of PI4K, GTPases, and their effectors is unknown. Here, we describe structures of PI4Kbeta (PI4KIIIbeta) bound to the small GTPase Rab11a without and with the Rab11 effector protein FIP3. The Rab11-PI4KIIIbeta interface is distinct compared with known structures of Rab complexes and does not involve switch regions used by GTPase effectors. Our data provide a mechanism for how PI4KIIIbeta coordinates Rab11 and its effectors on PI4P-enriched membranes and also provide strategies for the design of specific inhibitors that could potentially target plasmodial PI4KIIIbeta to combat malaria.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046302/" 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/PMC4046302/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Burke, John E -- Inglis, Alison J -- Perisic, Olga -- Masson, Glenn R -- McLaughlin, Stephen H -- Rutaganira, Florentine -- Shokat, Kevan M -- Williams, Roger L -- MC_U105184308/Medical Research Council/United Kingdom -- PG/11/109/29247/British Heart Foundation/United Kingdom -- PG11/109/29247/British Heart Foundation/United Kingdom -- R01AI099245/AI/NIAID NIH HHS/ -- T32 GM064337/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 May 30;344(6187):1035-8. doi: 10.1126/science.1253397.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. jeburke@uvic.ca rlw@mrc-lmb.cam.ac.uk. ; Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. ; Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24876499" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Antimalarials/chemistry/pharmacology ; Binding Sites ; Cell Line ; Crystallography, X-Ray ; Drug Design ; Humans ; I-kappa B Kinase/*chemistry ; Molecular Sequence Data ; Mutation ; Phosphotransferases (Alcohol Group Acceptor)/*chemistry/genetics ; Plasmodium/drug effects/growth & development ; Protein Binding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; rab GTP-Binding Proteins/*chemistry
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  • 34
    Publication Date: 2014-01-11
    Description: It has been assumed that most, if not all, signals regulating early development have been identified. Contrary to this expectation, we identified 28 candidate signaling proteins expressed during zebrafish embryogenesis, including Toddler, a short, conserved, and secreted peptide. Both absence and overproduction of Toddler reduce the movement of mesendodermal cells during zebrafish gastrulation. Local and ubiquitous production of Toddler promote cell movement, suggesting that Toddler is neither an attractant nor a repellent but acts globally as a motogen. Toddler drives internalization of G protein-coupled APJ/Apelin receptors, and activation of APJ/Apelin signaling rescues toddler mutants. These results indicate that Toddler is an activator of APJ/Apelin receptor signaling, promotes gastrulation movements, and might be the first in a series of uncharacterized developmental signals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107353/" 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/PMC4107353/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pauli, Andrea -- Norris, Megan L -- Valen, Eivind -- Chew, Guo-Liang -- Gagnon, James A -- Zimmerman, Steven -- Mitchell, Andrew -- Ma, Jiao -- Dubrulle, Julien -- Reyon, Deepak -- Tsai, Shengdar Q -- Joung, J Keith -- Saghatelian, Alan -- Schier, Alexander F -- K99 HD076935/HD/NICHD NIH HHS/ -- R01 GM056211/GM/NIGMS NIH HHS/ -- R01 GM102491/GM/NIGMS NIH HHS/ -- R01 HG005111/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Feb 14;343(6172):1248636. doi: 10.1126/science.1248636. Epub 2014 Jan 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24407481" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; *Cell Movement ; Chemokine CXCL12/metabolism ; Frameshift Mutation ; Gastrulation/genetics/*physiology ; Molecular Sequence Data ; Receptors, G-Protein-Coupled/genetics/*metabolism ; Signal Transduction ; Zebrafish/*embryology/genetics/metabolism ; Zebrafish Proteins/genetics/*metabolism
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  • 35
    Publication Date: 2014-10-18
    Description: Small molecules are useful tools for probing the biological function and therapeutic potential of individual proteins, but achieving selectivity is challenging when the target protein shares structural domains with other proteins. The Bromo and Extra-Terminal (BET) proteins have attracted interest because of their roles in transcriptional regulation, epigenetics, and cancer. The BET bromodomains (protein interaction modules that bind acetyl-lysine) have been targeted by potent small-molecule inhibitors, but these inhibitors lack selectivity for individual family members. We developed an ethyl derivative of an existing small-molecule inhibitor, I-BET/JQ1, and showed that it binds leucine/alanine mutant bromodomains with nanomolar affinity and achieves up to 540-fold selectivity relative to wild-type bromodomains. Cell culture studies showed that blockade of the first bromodomain alone is sufficient to displace a specific BET protein, Brd4, from chromatin. Expansion of this approach could help identify the individual roles of single BET proteins in human physiology and disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458378/" 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/PMC4458378/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baud, Matthias G J -- Lin-Shiao, Enrique -- Cardote, Teresa -- Tallant, Cynthia -- Pschibul, Annica -- Chan, Kwok-Ho -- Zengerle, Michael -- Garcia, Jordi R -- Kwan, Terence T-L -- Ferguson, Fleur M -- Ciulli, Alessio -- 097945/Z/11/Z/Wellcome Trust/United Kingdom -- 100476/Z/12/Z/Wellcome Trust/United Kingdom -- BB/G023123/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/J001201/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Oct 31;346(6209):638-41. doi: 10.1126/science.1249830. Epub 2014 Oct 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. ; Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK. ; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. ; Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. a.ciulli@dundee.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25323695" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Azepines/chemistry/pharmacology ; Cell Line, Tumor ; Chromatin/chemistry ; Crystallography, X-Ray ; Humans ; Leucine/genetics ; Models, Molecular ; Molecular Probes/*chemistry ; Mutation ; Nuclear Proteins/antagonists & inhibitors/*chemistry/genetics ; Protein Engineering/*methods ; Protein Structure, Tertiary ; Transcription Factors/antagonists & inhibitors/*chemistry/genetics ; Triazoles/chemistry/pharmacology
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  • 36
    Publication Date: 2014-11-22
    Description: Through their association with a kleisin subunit (Scc1), cohesin's Smc1 and Smc3 subunits are thought to form tripartite rings that mediate sister chromatid cohesion. Unlike the structure of Smc1/Smc3 and Smc1/Scc1 interfaces, that of Smc3/Scc1 is not known. Disconnection of this interface is thought to release cohesin from chromosomes in a process regulated by acetylation. We show here that the N-terminal domain of yeast Scc1 contains two alpha helices, forming a four-helix bundle with the coiled coil emerging from Smc3's adenosine triphosphatase head. Mutations affecting this interaction compromise cohesin's association with chromosomes. The interface is far from Smc3 residues, whose acetylation prevents cohesin's dissociation from chromosomes. Cohesin complexes holding chromatids together in vivo do indeed have the configuration of hetero-trimeric rings, and sister DNAs are entrapped within these.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300515/" 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/PMC4300515/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gligoris, Thomas G -- Scheinost, Johanna C -- Burmann, Frank -- Petela, Naomi -- Chan, Kok-Lung -- Uluocak, Pelin -- Beckouet, Frederic -- Gruber, Stephan -- Nasmyth, Kim -- Lowe, Jan -- 091859/Z/10/Z/Wellcome Trust/United Kingdom -- 095514/Wellcome Trust/United Kingdom -- 095514/Z/11/Z/Wellcome Trust/United Kingdom -- C573/A 12386/Cancer Research UK/United Kingdom -- C573/A11625/Medical Research Council/United Kingdom -- MC_U105184326/Medical Research Council/United Kingdom -- U10518432/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Nov 21;346(6212):963-7. doi: 10.1126/science.1256917.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK. ; Max-Planck-Institut fur Biochemie, 82152, Martinsried, Germany. ; Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK. Medical Research Council (MRC) Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK. ; Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK. Dunn School of Pathology, University of Oxford, Oxford OX1 3RF, UK. ; Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK. kim.nasmyth@bioch.ox.ac.uk jyl@mrc-lmb.cam.ac.uk. ; MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK. kim.nasmyth@bioch.ox.ac.uk jyl@mrc-lmb.cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25414305" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/chemistry ; Amino Acid Sequence ; Cell Cycle Proteins/*chemistry/genetics ; Chromosomal Proteins, Non-Histone/*chemistry/genetics ; Conserved Sequence ; Cross-Linking Reagents/chemistry ; Crystallography, X-Ray ; DNA/chemistry ; Mutation ; Protein Multimerization ; Protein Structure, Tertiary ; Saccharomyces cerevisiae Proteins/*chemistry/genetics
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  • 37
    Publication Date: 2014-12-20
    Description: Evolution and design of protein complexes are almost always viewed through the lens of amino acid mutations at protein interfaces. We showed previously that residues not involved in the physical interaction between proteins make important contributions to oligomerization by acting indirectly or allosterically. In this work, we sought to investigate the mechanism by which allosteric mutations act, using the example of the PyrR family of pyrimidine operon attenuators. In this family, a perfectly sequence-conserved helix that forms a tetrameric interface is exposed as solvent-accessible surface in dimeric orthologs. This means that mutations must be acting from a distance to destabilize the interface. We identified 11 key mutations controlling oligomeric state, all distant from the interfaces and outside ligand-binding pockets. Finally, we show that the key mutations introduce conformational changes equivalent to the conformational shift between the free versus nucleotide-bound conformations of the proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337988/" 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/PMC4337988/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perica, Tina -- Kondo, Yasushi -- Tiwari, Sandhya P -- McLaughlin, Stephen H -- Kemplen, Katherine R -- Zhang, Xiuwei -- Steward, Annette -- Reuter, Nathalie -- Clarke, Jane -- Teichmann, Sarah A -- 095195/Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2014 Dec 19;346(6216):1254346. doi: 10.1126/science.1254346.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. Medical Research Council (MRC) Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. ; Medical Research Council (MRC) Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. ; Department of Molecular Biology, University of Bergen University of Bergen, P.O. Box 7803, N-5020 Bergen, Norway. Computational Biology Unit, Department of Informatics, University of Bergen, P.O. Box 7803, N-5020 Bergen, Norway. ; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. ; European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. ; European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. saraht@ebi.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25525255" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation/*genetics ; Amino Acid Sequence ; Bacillus subtilis/metabolism ; Bacterial Proteins/*chemistry/genetics ; Conserved Sequence ; *Evolution, Molecular ; Ligands ; Mutation ; Pentosyltransferases/*chemistry/genetics ; Protein Binding/genetics ; Protein Conformation ; *Protein Engineering ; Protein Multimerization/*genetics ; Repressor Proteins/*chemistry/genetics
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  • 38
    Publication Date: 2014-04-20
    Description: Tight junctions are cell-cell adhesion structures in epithelial cell sheets that surround organ compartments in multicellular organisms and regulate the permeation of ions through the intercellular space. Claudins are the major constituents of tight junctions and form strands that mediate cell adhesion and function as paracellular barriers. We report the structure of mammalian claudin-15 at a resolution of 2.4 angstroms. The structure reveals a characteristic beta-sheet fold comprising two extracellular segments, which is anchored to a transmembrane four-helix bundle by a consensus motif. Our analyses suggest potential paracellular pathways with distinctive charges on the extracellular surface, providing insight into the molecular basis of ion homeostasis across tight junctions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Suzuki, Hiroshi -- Nishizawa, Tomohiro -- Tani, Kazutoshi -- Yamazaki, Yuji -- Tamura, Atsushi -- Ishitani, Ryuichiro -- Dohmae, Naoshi -- Tsukita, Sachiko -- Nureki, Osamu -- Fujiyoshi, Yoshinori -- New York, N.Y. -- Science. 2014 Apr 18;344(6181):304-7. doi: 10.1126/science.1248571.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cellular and Structural Physiology Institute, Nagoya University, Chikusa, Nagoya 464-8601, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24744376" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Claudins/*chemistry ; Crystallography, X-Ray ; Mice ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; Protein Folding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Protein Subunits/chemistry ; Static Electricity ; Tight Junctions/*chemistry/physiology
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  • 39
    Publication Date: 2014-08-16
    Description: Natural interconversions between distinct somatic cell types have been reported in species as diverse as jellyfish and mice. The efficiency and reproducibility of some reprogramming events represent unexploited avenues in which to probe mechanisms that ensure robust cell conversion. We report that a conserved H3K27me3/me2 demethylase, JMJD-3.1, and the H3K4 methyltransferase Set1 complex cooperate to ensure invariant transdifferentiation (Td) of postmitotic Caenorhabditis elegans hindgut cells into motor neurons. At single-cell resolution, robust conversion requires stepwise histone-modifying activities, functionally partitioned into discrete phases of Td through nuclear degradation of JMJD-3.1 and phase-specific interactions with transcription factors that have conserved roles in cell plasticity and terminal fate selection. Our results draw parallels between epigenetic mechanisms underlying robust Td in nature and efficient cell reprogramming in vitro.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zuryn, Steven -- Ahier, Arnaud -- Portoso, Manuela -- White, Esther Redhouse -- Morin, Marie-Charlotte -- Margueron, Raphael -- Jarriault, Sophie -- New York, N.Y. -- Science. 2014 Aug 15;345(6198):826-9. doi: 10.1126/science.1255885.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Development and Stem Cells, Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS UMR 7104/INSERM U964, Universite de Strasbourg, 67404 Illkirch CU Strasbourg, France. ; Institut Curie, INSERM U934, CNRS UMR3215, 26, Rue d'Ulm, 75005 Paris, France. ; Department of Development and Stem Cells, Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS UMR 7104/INSERM U964, Universite de Strasbourg, 67404 Illkirch CU Strasbourg, France. sophie@igbmc.fr.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25124442" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Animals, Genetically Modified ; Caenorhabditis elegans/*cytology/genetics ; Caenorhabditis elegans Proteins/chemistry/genetics/*metabolism ; Cell Dedifferentiation ; Cell Nucleus/metabolism/ultrastructure ; *Cell Transdifferentiation ; Digestive System/cytology ; Histone Demethylases/chemistry/genetics/*metabolism ; Histone-Lysine N-Methyltransferase/genetics/*metabolism ; Histones/*metabolism ; Lysine/metabolism ; Methylation ; Models, Biological ; Molecular Sequence Data ; Motor Neurons/*cytology ; Transcription Factors/metabolism
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  • 40
    Publication Date: 2014-12-17
    Description: Iron sequestration provides an innate defense, termed nutritional immunity, leading pathogens to scavenge iron from hosts. Although the molecular basis of this battle for iron is established, its potential as a force for evolution at host-pathogen interfaces is unknown. We show that the iron transport protein transferrin is engaged in ancient and ongoing evolutionary conflicts with TbpA, a transferrin surface receptor from bacteria. Single substitutions in transferrin at rapidly evolving sites reverse TbpA binding, providing a mechanism to counteract bacterial iron piracy among great apes. Furthermore, the C2 transferrin polymorphism in humans evades TbpA variants from Haemophilus influenzae, revealing a functional basis for standing genetic variation. These findings identify a central role for nutritional immunity in the persistent evolutionary conflicts between primates and bacterial pathogens.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4455941/" 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/PMC4455941/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barber, Matthew F -- Elde, Nels C -- 1F32GM108288/GM/NIGMS NIH HHS/ -- GM090042/GM/NIGMS NIH HHS/ -- R00 GM090042/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Dec 12;346(6215):1362-6. doi: 10.1126/science.1259329.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. ; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. nelde@genetics.utah.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25504720" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Evolution, Molecular ; Haemophilus influenzae/*metabolism ; Haplorhini/*genetics/immunology/*metabolism ; Humans ; Immunity, Innate ; Models, Molecular ; Molecular Sequence Data ; Neisseria/*metabolism ; Neisseria gonorrhoeae/metabolism ; Neisseria meningitidis/metabolism ; Phylogeny ; Polymorphism, Genetic ; Protein Binding ; Selection, Genetic ; Transferrin/chemistry/*genetics/*metabolism ; Transferrin-Binding Protein A/chemistry/*genetics/*metabolism
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  • 41
    Publication Date: 2014-06-21
    Description: Primate lentiviruses exhibit narrow host tropism, reducing the occurrence of zoonoses but also impairing the development of optimal animal models of AIDS. To delineate the factors limiting cross-species HIV-1 transmission, we passaged a modified HIV-1 in pigtailed macaques that were transiently depleted of CD8(+) cells during acute infection. During adaptation over four passages in macaques, HIV-1 acquired the ability to antagonize the macaque restriction factor tetherin, replicated at progressively higher levels, and ultimately caused marked CD4(+) T cell depletion and AIDS-defining conditions. Transient treatment with an antibody to CD8 during acute HIV-1 infection caused rapid progression to AIDS, whereas untreated animals exhibited an elite controller phenotype. Thus, an adapted HIV-1 can cause AIDS in macaques, and stark differences in outcome can be determined by immunological perturbations during early infection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266393/" 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/PMC4266393/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hatziioannou, Theodora -- Del Prete, Gregory Q -- Keele, Brandon F -- Estes, Jacob D -- McNatt, Matthew W -- Bitzegeio, Julia -- Raymond, Alice -- Rodriguez, Anthony -- Schmidt, Fabian -- Mac Trubey, C -- Smedley, Jeremy -- Piatak, Michael Jr -- KewalRamani, Vineet N -- Lifson, Jeffrey D -- Bieniasz, Paul D -- HHSN261200800001E/PHS HHS/ -- R01 AI050111/AI/NIAID NIH HHS/ -- R01 AI078788/AI/NIAID NIH HHS/ -- R01AI078788/AI/NIAID NIH HHS/ -- R01AI50111/AI/NIAID NIH HHS/ -- R37 AI064003/AI/NIAID NIH HHS/ -- R37AI64003/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Jun 20;344(6190):1401-5. doi: 10.1126/science.1250761.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Aaron Diamond AIDS Research Center, 455 First Avenue, New York, NY 10016, USA. thatziio@adarc.org vineet.kewalramani@nih.gov lifsonj@mail.nih.gov pbienias@adarc.org. ; AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory, Frederick, MD 21702, USA. ; Aaron Diamond AIDS Research Center, 455 First Avenue, New York, NY 10016, USA. Laboratory of Retrovirology, The Rockefeller University, 455 First Avenue, New York, NY 10016, USA. ; Aaron Diamond AIDS Research Center, 455 First Avenue, New York, NY 10016, USA. ; Laboratory Animal Sciences Program, Leidos Biomedical Research, Frederick National Laboratory, Frederick, MD 21702, USA. ; HIV Drug Resistance Program, National Cancer Institute, Frederick, MD 21702, USA. thatziio@adarc.org vineet.kewalramani@nih.gov lifsonj@mail.nih.gov pbienias@adarc.org. ; AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory, Frederick, MD 21702, USA. thatziio@adarc.org vineet.kewalramani@nih.gov lifsonj@mail.nih.gov pbienias@adarc.org. ; Aaron Diamond AIDS Research Center, 455 First Avenue, New York, NY 10016, USA. Laboratory of Retrovirology, The Rockefeller University, 455 First Avenue, New York, NY 10016, USA. Howard Hughes Medical Institute, 455 First Avenue, New York, NY 10016, USA. thatziio@adarc.org vineet.kewalramani@nih.gov lifsonj@mail.nih.gov pbienias@adarc.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24948736" target="_blank"〉PubMed〈/a〉
    Keywords: Acquired Immunodeficiency Syndrome/immunology/transmission/*virology ; Amino Acid Sequence ; Animals ; Antigens, CD8/immunology ; CD4-Positive T-Lymphocytes/immunology ; *Disease Models, Animal ; HIV-1/genetics/*physiology ; Host-Pathogen Interactions/*immunology ; Human Immunodeficiency Virus Proteins/chemistry/genetics/metabolism ; Lymphocyte Depletion ; Macaca nemestrina/immunology/*virology ; Molecular Sequence Data ; Protein Structure, Tertiary ; Viral Regulatory and Accessory Proteins/chemistry/genetics/metabolism ; Virus Replication
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  • 42
    Publication Date: 2014-03-22
    Description: Under resting conditions, Pink1 knockout cells and cells derived from patients with PINK1 mutations display a loss of mitochondrial complex I reductive activity, causing a decrease in the mitochondrial membrane potential. Analyzing the phosphoproteome of complex I in liver and brain from Pink1(-/-) mice, we found specific loss of phosphorylation of serine-250 in complex I subunit NdufA10. Phosphorylation of serine-250 was needed for ubiquinone reduction by complex I. Phosphomimetic NdufA10 reversed Pink1 deficits in mouse knockout cells and rescued mitochondrial depolarization and synaptic transmission defects in pink(B9)-null mutant Drosophila. Complex I deficits and adenosine triphosphate synthesis were also rescued in cells derived from PINK1 patients. Thus, this evolutionary conserved pathway may contribute to the pathogenic cascade that eventually leads to Parkinson's disease in patients with PINK1 mutations.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Morais, Vanessa A -- Haddad, Dominik -- Craessaerts, Katleen -- De Bock, Pieter-Jan -- Swerts, Jef -- Vilain, Sven -- Aerts, Liesbeth -- Overbergh, Lut -- Grunewald, Anne -- Seibler, Philip -- Klein, Christine -- Gevaert, Kris -- Verstreken, Patrik -- De Strooper, Bart -- New York, N.Y. -- Science. 2014 Apr 11;344(6180):203-7. doi: 10.1126/science.1249161. Epub 2014 Mar 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉VIB Center for the Biology of Disease, 3000 Leuven, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24652937" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Brain/enzymology ; Drosophila Proteins/*metabolism ; Electron Transport Complex I/*metabolism ; Humans ; Liver/enzymology ; Membrane Potential, Mitochondrial/genetics ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Mutation ; NADH Dehydrogenase/*metabolism ; Parkinson Disease/*enzymology/*genetics ; Phosphorylation/genetics ; Protein Kinases/*genetics ; Proteome ; Serine/chemistry/metabolism
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  • 43
    Publication Date: 2014-05-17
    Description: Signaling from JAK (Janus kinase) protein kinases to STAT (signal transducers and activators of transcription) transcription factors is key to many aspects of biology and medicine, yet the mechanism by which cytokine receptors initiate signaling is enigmatic. We present a complete mechanistic model for activation of receptor-bound JAK2, based on an archetypal cytokine receptor, the growth hormone receptor. For this, we used fluorescence resonance energy transfer to monitor positioning of the JAK2 binding motif in the receptor dimer, substitution of the receptor extracellular domains with Jun zippers to control the position of its transmembrane (TM) helices, atomistic modeling of TM helix movements, and docking of the crystal structures of the JAK2 kinase and its inhibitory pseudokinase domain with an opposing kinase-pseudokinase domain pair. Activation of the receptor dimer induced a separation of its JAK2 binding motifs, driven by a ligand-induced transition from a parallel TM helix pair to a left-handed crossover arrangement. This separation leads to removal of the pseudokinase domain from the kinase domain of the partner JAK2 and pairing of the two kinase domains, facilitating trans-activation. This model may well generalize to other class I cytokine receptors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brooks, Andrew J -- Dai, Wei -- O'Mara, Megan L -- Abankwa, Daniel -- Chhabra, Yash -- Pelekanos, Rebecca A -- Gardon, Olivier -- Tunny, Kathryn A -- Blucher, Kristopher M -- Morton, Craig J -- Parker, Michael W -- Sierecki, Emma -- Gambin, Yann -- Gomez, Guillermo A -- Alexandrov, Kirill -- Wilson, Ian A -- Doxastakis, Manolis -- Mark, Alan E -- Waters, Michael J -- New York, N.Y. -- Science. 2014 May 16;344(6185):1249783. doi: 10.1126/science.1249783.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The University of Queensland, Institute for Molecular Bioscience (IMB), St Lucia, Queensland 4072, Australia. m.waters@uq.edu.au a.brooks@uq.edu.au. ; Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77004, USA. ; The University of Queensland, School of Chemistry and Molecular Biosciences, St Lucia, Queensland 4072, Australia. ; The University of Queensland, Institute for Molecular Bioscience (IMB), St Lucia, Queensland 4072, Australia. ; Biota Structural Biology Laboratory and Australian Cancer Research Foundation (ACRF) Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia. ; Biota Structural Biology Laboratory and Australian Cancer Research Foundation (ACRF) Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia. Department of Biochemistry and Molecular Biology and Bio21 Institute, University of Melbourne, Parkville, Victoria 3052, Australia. ; Scripps Research Institute, La Jolla, CA 92037, USA. ; The University of Queensland, Institute for Molecular Bioscience (IMB), St Lucia, Queensland 4072, Australia. The University of Queensland, School of Chemistry and Molecular Biosciences, St Lucia, Queensland 4072, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24833397" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Cysteine/chemistry ; Enzyme Activation ; HEK293 Cells ; Humans ; Janus Kinase 2/antagonists & inhibitors/chemistry/*metabolism ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, Somatotropin/chemistry/genetics/*metabolism
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  • 44
    Publication Date: 2014-02-18
    Description: In this work, we investigate morphological differences between Arabidopsis thaliana, which has simple leaves, and its relative Cardamine hirsuta, which has dissected leaves comprising distinct leaflets. With the use of genetics, interspecific gene transfers, and time-lapse imaging, we show that leaflet development requires the REDUCED COMPLEXITY (RCO) homeodomain protein. RCO functions specifically in leaves, where it sculpts developing leaflets by repressing growth at their flanks. RCO evolved in the Brassicaceae family through gene duplication and was lost in A. thaliana, contributing to leaf simplification in this species. Species-specific RCO action with respect to its paralog results from its distinct gene expression pattern in the leaf base. Thus, regulatory evolution coupled with gene duplication and loss generated leaf shape diversity by modifying local growth patterns during organogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vlad, Daniela -- Kierzkowski, Daniel -- Rast, Madlen I -- Vuolo, Francesco -- Dello Ioio, Raffaele -- Galinha, Carla -- Gan, Xiangchao -- Hajheidari, Mohsen -- Hay, Angela -- Smith, Richard S -- Huijser, Peter -- Bailey, C Donovan -- Tsiantis, Miltos -- BB/H006974/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/H011455/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Feb 14;343(6172):780-3. doi: 10.1126/science.1248384.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Plant Sciences, University of Oxford, South Parks Road, Oxford OX1 3RB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24531971" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arabidopsis/anatomy & histology/genetics ; Brassicaceae/*anatomy & histology/*genetics ; Chromosome Mapping ; *Evolution, Molecular ; Gene Duplication ; *Gene Expression Regulation, Plant ; *Genes, Homeobox ; Genetic Complementation Test ; Molecular Sequence Data ; Plant Leaves/*anatomy & histology/*genetics
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  • 45
    Publication Date: 2014-03-15
    Description: Histone variants have been proposed to act as determinants for posttranslational modifications with widespread regulatory functions. We identify a histone-modifying enzyme that selectively methylates the replication-dependent histone H3 variant H3.1. The crystal structure of the SET domain of the histone H3 lysine-27 (H3K27) methyltransferase ARABIDOPSIS TRITHORAX-RELATED PROTEIN 5 (ATXR5) in complex with a H3.1 peptide shows that ATXR5 contains a bipartite catalytic domain that specifically "reads" alanine-31 of H3.1. Variation at position 31 between H3.1 and replication-independent H3.3 is conserved in plants and animals, and threonine-31 in H3.3 is responsible for inhibiting the activity of ATXR5 and its paralog, ATXR6. Our results suggest a simple model for the mitotic inheritance of the heterochromatic mark H3K27me1 and the protection of H3.3-enriched genes against heterochromatization during DNA replication.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049228/" 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/PMC4049228/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jacob, Yannick -- Bergamin, Elisa -- Donoghue, Mark T A -- Mongeon, Vanessa -- LeBlanc, Chantal -- Voigt, Philipp -- Underwood, Charles J -- Brunzelle, Joseph S -- Michaels, Scott D -- Reinberg, Danny -- Couture, Jean-Francois -- Martienssen, Robert A -- BMA-355900/Canadian Institutes of Health Research/Canada -- GM064844/GM/NIGMS NIH HHS/ -- GM067014/GM/NIGMS NIH HHS/ -- GM075060/GM/NIGMS NIH HHS/ -- R01 GM067014/GM/NIGMS NIH HHS/ -- R01 GM075060/GM/NIGMS NIH HHS/ -- R37 GM037120/GM/NIGMS NIH HHS/ -- R37GM037120/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Mar 14;343(6176):1249-53. doi: 10.1126/science.1248357.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute-Gordon and Betty Moore Foundation, Watson School of Biological Sciences, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24626927" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arabidopsis/genetics/*metabolism ; Arabidopsis Proteins/*chemistry/metabolism ; Catalytic Domain ; Conserved Sequence ; Crystallography, X-Ray ; DNA Replication ; Epigenesis, Genetic ; Gene Expression Regulation, Plant ; Heterochromatin/*metabolism ; Histones/*metabolism ; Methylation ; Methyltransferases/*chemistry/metabolism ; Mitosis ; Molecular Sequence Data ; *Protein Processing, Post-Translational ; Threonine/metabolism
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  • 46
    Publication Date: 2014-06-28
    Description: Lassa virus spreads from a rodent to humans and can lead to lethal hemorrhagic fever. Despite its broad tropism, chicken cells were reported 30 years ago to resist infection. We found that Lassa virus readily engaged its cell-surface receptor alpha-dystroglycan in avian cells, but virus entry in susceptible species involved a pH-dependent switch to an intracellular receptor, the lysosome-resident protein LAMP1. Iterative haploid screens revealed that the sialyltransferase ST3GAL4 was required for the interaction of the virus glycoprotein with LAMP1. A single glycosylated residue in LAMP1, present in susceptible species but absent in birds, was essential for interaction with the Lassa virus envelope protein and subsequent infection. The resistance of Lamp1-deficient mice to Lassa virus highlights the relevance of this receptor switch in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239993/" 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/PMC4239993/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jae, Lucas T -- Raaben, Matthijs -- Herbert, Andrew S -- Kuehne, Ana I -- Wirchnianski, Ariel S -- Soh, Timothy K -- Stubbs, Sarah H -- Janssen, Hans -- Damme, Markus -- Saftig, Paul -- Whelan, Sean P -- Dye, John M -- Brummelkamp, Thijn R -- AI081842/AI/NIAID NIH HHS/ -- AI109740/AI/NIAID NIH HHS/ -- R01 AI081842/AI/NIAID NIH HHS/ -- T32 AI007245/AI/NIAID NIH HHS/ -- U19 AI109740/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2014 Jun 27;344(6191):1506-10. doi: 10.1126/science.1252480.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands. ; Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands. Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. ; U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702-5011, USA. ; Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. ; Biochemisches Institut, Christian Albrechts-Universitat Kiel, 24118 Kiel, Germany. ; Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. t.brummelkamp@nki.nl john.m.dye1.civ@mail.mil sean_whelan@hms.harvard.edu. ; U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702-5011, USA. t.brummelkamp@nki.nl john.m.dye1.civ@mail.mil sean_whelan@hms.harvard.edu. ; Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. Cancer Genomics Center (CGC.nl), Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands. t.brummelkamp@nki.nl john.m.dye1.civ@mail.mil sean_whelan@hms.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24970085" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Cell Line ; Cell Membrane/metabolism/virology ; Cells, Cultured ; Chickens ; Dystroglycans/genetics/metabolism ; Glycosylation ; Humans ; Hydrogen-Ion Concentration ; Lassa Fever/virology ; Lassa virus/*physiology ; Lysosomal-Associated Membrane Protein 1/chemistry/*metabolism ; Lysosomes/metabolism/virology ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Protein Binding ; Receptors, Virus/*metabolism ; Sialyltransferases/metabolism ; Viral Envelope Proteins/*metabolism ; *Virus Internalization
    Print ISSN: 0036-8075
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  • 47
    Publication Date: 2014-03-22
    Description: The 18-kilodalton translocator protein TSPO is found in mitochondrial membranes and mediates the import of cholesterol and porphyrins into mitochondria. In line with the role of TSPO in mitochondrial function, TSPO ligands are used for a variety of diagnostic and therapeutic applications in animals and humans. We present the three-dimensional high-resolution structure of mammalian TSPO reconstituted in detergent micelles in complex with its high-affinity ligand PK11195. The TSPO-PK11195 structure is described by a tight bundle of five transmembrane alpha helices that form a hydrophobic pocket accepting PK11195. Ligand-induced stabilization of the structure of TSPO suggests a molecular mechanism for the stimulation of cholesterol transport into mitochondria.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jaremko, Lukasz -- Jaremko, Mariusz -- Giller, Karin -- Becker, Stefan -- Zweckstetter, Markus -- New York, N.Y. -- Science. 2014 Mar 21;343(6177):1363-6. doi: 10.1126/science.1248725.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max-Planck-Institut fur Biophysikalische Chemie, 37077 Gottingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24653034" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Binding Sites ; Biological Transport ; Cholesterol/metabolism ; Hydrophobic and Hydrophilic Interactions ; Isoquinolines/*chemistry/metabolism ; Ligands ; Mice ; Micelles ; Mitochondria/metabolism ; Mitochondrial Membrane Transport Proteins/*chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Nuclear Magnetic Resonance, Biomolecular ; Protein Binding ; Protein Conformation ; Protein Structure, Secondary ; Receptors, GABA/*chemistry/metabolism ; Recombinant Proteins/chemistry/metabolism
    Print ISSN: 0036-8075
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  • 48
    Publication Date: 2014-06-07
    Description: Sheep (Ovis aries) are a major source of meat, milk, and fiber in the form of wool and represent a distinct class of animals that have a specialized digestive organ, the rumen, that carries out the initial digestion of plant material. We have developed and analyzed a high-quality reference sheep genome and transcriptomes from 40 different tissues. We identified highly expressed genes encoding keratin cross-linking proteins associated with rumen evolution. We also identified genes involved in lipid metabolism that had been amplified and/or had altered tissue expression patterns. This may be in response to changes in the barrier lipids of the skin, an interaction between lipid metabolism and wool synthesis, and an increased role of volatile fatty acids in ruminants compared with nonruminant animals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157056/" 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/PMC4157056/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Yu -- Xie, Min -- Chen, Wenbin -- Talbot, Richard -- Maddox, Jillian F -- Faraut, Thomas -- Wu, Chunhua -- Muzny, Donna M -- Li, Yuxiang -- Zhang, Wenguang -- Stanton, Jo-Ann -- Brauning, Rudiger -- Barris, Wesley C -- Hourlier, Thibaut -- Aken, Bronwen L -- Searle, Stephen M J -- Adelson, David L -- Bian, Chao -- Cam, Graham R -- Chen, Yulin -- Cheng, Shifeng -- DeSilva, Udaya -- Dixen, Karen -- Dong, Yang -- Fan, Guangyi -- Franklin, Ian R -- Fu, Shaoyin -- Fuentes-Utrilla, Pablo -- Guan, Rui -- Highland, Margaret A -- Holder, Michael E -- Huang, Guodong -- Ingham, Aaron B -- Jhangiani, Shalini N -- Kalra, Divya -- Kovar, Christie L -- Lee, Sandra L -- Liu, Weiqing -- Liu, Xin -- Lu, Changxin -- Lv, Tian -- Mathew, Tittu -- McWilliam, Sean -- Menzies, Moira -- Pan, Shengkai -- Robelin, David -- Servin, Bertrand -- Townley, David -- Wang, Wenliang -- Wei, Bin -- White, Stephen N -- Yang, Xinhua -- Ye, Chen -- Yue, Yaojing -- Zeng, Peng -- Zhou, Qing -- Hansen, Jacob B -- Kristiansen, Karsten -- Gibbs, Richard A -- Flicek, Paul -- Warkup, Christopher C -- Jones, Huw E -- Oddy, V Hutton -- Nicholas, Frank W -- McEwan, John C -- Kijas, James W -- Wang, Jun -- Worley, Kim C -- Archibald, Alan L -- Cockett, Noelle -- Xu, Xun -- Wang, Wen -- Dalrymple, Brian P -- 095908/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- BB/1025360/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/I025328/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/I025360/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/I025506/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- U54 HG003273/HG/NHGRI NIH HHS/ -- WT095908/Wellcome Trust/United Kingdom -- WT098051/Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2014 Jun 6;344(6188):1168-73. doi: 10.1126/science.1252806.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China. Commonwealth Scientific and Industrial Research Organisation Animal Food and Health Sciences, St Lucia, QLD 4067, Australia. College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China. ; BGI-Shenzhen, Shenzhen 518083, China. ; Ediburgh Genomics, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK. ; Utah State University, Logan, UT 84322-4815, USA. ; Institut National de la Recherche Agronomique, Laboratoire de Genetique Cellulaire, UMR 444, Castanet-Tolosan F-31326, France. ; Utah State University, Logan, UT 84322-1435, USA. ; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. ; State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China. Inner Mongolia Agricultural University, Hohhot 010018, China. Institute of ATCG, Nei Mongol Bio-Information, Hohhot, China. ; Department of Anatomy, University of Otago, Dunedin 9054, New Zealand. ; AgResearch, Invermay Agricultural Centre, Mosgiel 9053, New Zealand. ; Commonwealth Scientific and Industrial Research Organisation Animal Food and Health Sciences, St Lucia, QLD 4067, Australia. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK. ; College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China. ; Department of Biology, University of Copenhagen, DK-2100 Copenhagen O, Denmark. ; State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China. ; Inner Mongolia Agricultural University, Hohhot 010018, China. ; U.S. Department of Agriculture Agricultural Research Service Animal Disease Research Unit, Pullman, WA 99164, USA. Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164, USA. ; BGI-Shenzhen, Shenzhen 518083, China. Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China. ; Lanzhou Institute of Husbandry and Pharmaceutical Science, Lanzhou, 730050, China. ; Department of Biology, University of Copenhagen, DK-2200 Copenhagen N, Denmark. ; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK. ; Biosciences Knowledge Transfer Network, The Roslin Institute, Easter Bush, Midlothian, EH25 9RG, UK. ; School of Environmental and Rural Science, University of New England, Armidale, NSW 2351, Australia. ; Faculty of Veterinary Science, University of Sydney, NSW 2006, Australia. ; BGI-Shenzhen, Shenzhen 518083, China. Department of Biology, University of Copenhagen, DK-2200 Copenhagen N, Denmark. Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia. Macau University of Science and Technology, Macau 999078, China. ; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. brian.dalrymple@csiro.au wwang@mail.kiz.ac.cn xuxun@genomics.cn alan.archibald@roslin.ed.ac.uk kworley@bcm.edu noelle.cockett@usu.edu. ; The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK. brian.dalrymple@csiro.au wwang@mail.kiz.ac.cn xuxun@genomics.cn alan.archibald@roslin.ed.ac.uk kworley@bcm.edu noelle.cockett@usu.edu. ; Utah State University, Logan, UT 84322-1435, USA. brian.dalrymple@csiro.au wwang@mail.kiz.ac.cn xuxun@genomics.cn alan.archibald@roslin.ed.ac.uk kworley@bcm.edu noelle.cockett@usu.edu. ; BGI-Shenzhen, Shenzhen 518083, China. brian.dalrymple@csiro.au wwang@mail.kiz.ac.cn xuxun@genomics.cn alan.archibald@roslin.ed.ac.uk kworley@bcm.edu noelle.cockett@usu.edu. ; State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China. brian.dalrymple@csiro.au wwang@mail.kiz.ac.cn xuxun@genomics.cn alan.archibald@roslin.ed.ac.uk kworley@bcm.edu noelle.cockett@usu.edu. ; Commonwealth Scientific and Industrial Research Organisation Animal Food and Health Sciences, St Lucia, QLD 4067, Australia. brian.dalrymple@csiro.au wwang@mail.kiz.ac.cn xuxun@genomics.cn alan.archibald@roslin.ed.ac.uk kworley@bcm.edu noelle.cockett@usu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24904168" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Fatty Acids, Volatile/metabolism/physiology ; Gene Expression Regulation ; Genome ; Keratins, Hair-Specific/genetics ; Lipid Metabolism/genetics/*physiology ; Molecular Sequence Data ; Phylogeny ; Rumen/metabolism/*physiology ; Sheep, Domestic/classification/*genetics/*metabolism ; Transcriptome ; Wool/growth & development
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  • 49
    Publication Date: 2014-02-08
    Description: Type II CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) systems use an RNA-guided DNA endonuclease, Cas9, to generate double-strand breaks in invasive DNA during an adaptive bacterial immune response. Cas9 has been harnessed as a powerful tool for genome editing and gene regulation in many eukaryotic organisms. We report 2.6 and 2.2 angstrom resolution crystal structures of two major Cas9 enzyme subtypes, revealing the structural core shared by all Cas9 family members. The architectures of Cas9 enzymes define nucleic acid binding clefts, and single-particle electron microscopy reconstructions show that the two structural lobes harboring these clefts undergo guide RNA-induced reorientation to form a central channel where DNA substrates are bound. The observation that extensive structural rearrangements occur before target DNA duplex binding implicates guide RNA loading as a key step in Cas9 activation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184034/" 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/PMC4184034/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jinek, Martin -- Jiang, Fuguo -- Taylor, David W -- Sternberg, Samuel H -- Kaya, Emine -- Ma, Enbo -- Anders, Carolin -- Hauer, Michael -- Zhou, Kaihong -- Lin, Steven -- Kaplan, Matias -- Iavarone, Anthony T -- Charpentier, Emmanuelle -- Nogales, Eva -- Doudna, Jennifer A -- T32 GM066698/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Mar 14;343(6176):1247997. doi: 10.1126/science.1247997. Epub 2014 Feb 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Zurich, CH-8057 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24505130" target="_blank"〉PubMed〈/a〉
    Keywords: Actinomyces/*enzymology ; Amino Acid Sequence ; Bacterial Proteins/*chemistry ; Caspase 9/*chemistry ; Crystallography, X-Ray ; DNA Cleavage ; Molecular Sequence Data ; Nucleic Acid Conformation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; RNA/*chemistry ; Streptococcus pyogenes/*enzymology
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  • 50
    Publication Date: 2014-12-06
    Description: Distinct types of CD4(+) T cells protect the host against different classes of pathogens. However, it is unclear whether a given pathogen induces a single type of polarized T cell. By combining antigenic stimulation and T cell receptor deep sequencing, we found that human pathogen- and vaccine-specific T helper 1 (T(H)1), T(H)2, and T(H)17 memory cells have different frequencies but comparable diversity and comprise not only clones polarized toward a single fate, but also clones whose progeny have acquired multiple fates. Single naive T cells primed by a pathogen in vitro could also give rise to multiple fates. Our results unravel an unexpected degree of interclonal and intraclonal functional heterogeneity of the human T cell response and suggest that polarized responses result from preferential expansion rather than priming.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Becattini, Simone -- Latorre, Daniela -- Mele, Federico -- Foglierini, Mathilde -- De Gregorio, Corinne -- Cassotta, Antonino -- Fernandez, Blanca -- Kelderman, Sander -- Schumacher, Ton N -- Corti, Davide -- Lanzavecchia, Antonio -- Sallusto, Federica -- New York, N.Y. -- Science. 2015 Jan 23;347(6220):400-6. doi: 10.1126/science.1260668. Epub 2014 Dec 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Research in Biomedicine, Bellinzona, Universita della Svizzera Italiana, Lugano, Switzerland. Institute of Microbiology, ETH Zurich, Zurich, Switzerland. ; Institute for Research in Biomedicine, Bellinzona, Universita della Svizzera Italiana, Lugano, Switzerland. ; Division of Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands. ; Institute for Research in Biomedicine, Bellinzona, Universita della Svizzera Italiana, Lugano, Switzerland. federica.sallusto@irb.usi.ch.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25477212" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; CD4-Positive T-Lymphocytes/*immunology ; Candida albicans/*immunology ; Cells, Cultured ; Clone Cells ; High-Throughput Nucleotide Sequencing ; Host-Pathogen Interactions/*immunology ; Humans ; *Immunologic Memory ; Lymphocyte Activation ; Molecular Sequence Data ; Mycobacterium tuberculosis/*immunology ; Receptors, Antigen, T-Cell/genetics ; T-Lymphocyte Subsets/*immunology ; Th1 Cells/immunology ; Th17 Cells/immunology ; Th2 Cells/immunology ; Vaccines/*immunology
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  • 51
    Publication Date: 2014-12-17
    Description: The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from 〈/=0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349400/" 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/PMC4349400/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Straimer, Judith -- Gnadig, Nina F -- Witkowski, Benoit -- Amaratunga, Chanaki -- Duru, Valentine -- Ramadani, Arba Pramundita -- Dacheux, Melanie -- Khim, Nimol -- Zhang, Lei -- Lam, Stephen -- Gregory, Philip D -- Urnov, Fyodor D -- Mercereau-Puijalon, Odile -- Benoit-Vical, Francoise -- Fairhurst, Rick M -- Menard, Didier -- Fidock, David A -- R01 AI109023/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 23;347(6220):428-31. doi: 10.1126/science.1260867. Epub 2014 Dec 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY, USA. ; Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia. ; Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. ; Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie de Coordination UPR8241, Toulouse, France. Universite de Toulouse, UPS, Institut National Polytechnique de Toulouse, Toulouse, France. ; Sangamo BioSciences, Richmond, CA, USA. ; Institut Pasteur, Parasite Molecular Immunology Unit, Paris, France. ; Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY, USA. Division of Infectious Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA. df2260@columbia.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25502314" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Antimalarials/*pharmacology ; Artemisinins/*pharmacology ; Cambodia ; Drug Resistance/*genetics ; Genetic Loci ; Humans ; Malaria, Falciparum/drug therapy/parasitology ; Molecular Sequence Data ; Mutation ; Plasmodium falciparum/*drug effects/*genetics ; Protein Structure, Tertiary ; Protozoan Proteins/chemistry/*genetics
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  • 52
    Publication Date: 2014-12-04
    Description: Contusive spinal cord injury leads to a variety of disabilities owing to limited neuronal regeneration and functional plasticity. It is well established that an upregulation of glial-derived chondroitin sulphate proteoglycans (CSPGs) within the glial scar and perineuronal net creates a barrier to axonal regrowth and sprouting. Protein tyrosine phosphatase sigma (PTPsigma), along with its sister phosphatase leukocyte common antigen-related (LAR) and the nogo receptors 1 and 3 (NgR), have recently been identified as receptors for the inhibitory glycosylated side chains of CSPGs. Here we find in rats that PTPsigma has a critical role in converting growth cones into a dystrophic state by tightly stabilizing them within CSPG-rich substrates. We generated a membrane-permeable peptide mimetic of the PTPsigma wedge domain that binds to PTPsigma and relieves CSPG-mediated inhibition. Systemic delivery of this peptide over weeks restored substantial serotonergic innervation to the spinal cord below the level of injury and facilitated functional recovery of both locomotor and urinary systems. Our results add a new layer of understanding to the critical role of PTPsigma in mediating the growth-inhibited state of neurons due to CSPGs within the injured adult spinal cord.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336236/" 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/PMC4336236/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lang, Bradley T -- Cregg, Jared M -- DePaul, Marc A -- Tran, Amanda P -- Xu, Kui -- Dyck, Scott M -- Madalena, Kathryn M -- Brown, Benjamin P -- Weng, Yi-Lan -- Li, Shuxin -- Karimi-Abdolrezaee, Soheila -- Busch, Sarah A -- Shen, Yingjie -- Silver, Jerry -- NS025713/NS/NINDS NIH HHS/ -- R01 EY024575/EY/NEI NIH HHS/ -- R01 NS025713/NS/NINDS NIH HHS/ -- R01 NS079432/NS/NINDS NIH HHS/ -- England -- Nature. 2015 Feb 19;518(7539):404-8. doi: 10.1038/nature13974. Epub 2014 Dec 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. ; Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center at The Ohio State University, Columbus, Ohio 43210, USA. ; Regenerative Medicine Program and Department of Physiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada. ; Baldwin Wallace University, Berea, Ohio 44017, USA. ; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA. ; Shriners Hospital's Pediatric Research Center (Center for Neural Repair and Rehabilitation), Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470046" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Chondroitin Sulfate Proteoglycans/*metabolism ; Extracellular Matrix/chemistry/drug effects/metabolism ; Female ; Growth Cones/drug effects/physiology ; Humans ; Mice ; Molecular Sequence Data ; *Nerve Regeneration/drug effects ; Protein Binding/drug effects ; Rats ; Rats, Sprague-Dawley ; Receptor-Like Protein Tyrosine Phosphatases, Class 2/antagonists & ; inhibitors/chemistry/*metabolism ; Spinal Cord Injuries/*metabolism/pathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
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  • 53
    Publication Date: 2014-09-16
    Description: The reprogramming of epigenetic states in gametes and embryos is essential for correct development in plants and mammals. In plants, the germ line arises from somatic tissues of the flower, necessitating the erasure of chromatin modifications that have accumulated at specific loci during development or in response to external stimuli. If this process occurs inefficiently, it can lead to epigenetic states being inherited from one generation to the next. However, in most cases, accumulated epigenetic modifications are efficiently erased before the next generation. An important example of epigenetic reprogramming in plants is the resetting of the expression of the floral repressor locus FLC in Arabidopsis thaliana. FLC is epigenetically silenced by prolonged cold in a process called vernalization. However, the locus is reactivated before the completion of seed development, ensuring the requirement for vernalization in every generation. In contrast to our detailed understanding of the polycomb-mediated epigenetic silencing induced by vernalization, little is known about the mechanism involved in the reactivation of FLC. Here we show that a hypomorphic mutation in the jumonji-domain-containing protein ELF6 impaired the reactivation of FLC in reproductive tissues, leading to the inheritance of a partially vernalized state. ELF6 has H3K27me3 demethylase activity, and the mutation reduced this enzymatic activity in planta. Consistent with this, in the next generation of mutant plants, H3K27me3 levels at the FLC locus stayed higher, and FLC expression remained lower, than in the wild type. Our data reveal an ancient role for H3K27 demethylation in the reprogramming of epigenetic states in plant and mammalian embryos.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4247276/" 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/PMC4247276/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Crevillen, Pedro -- Yang, Hongchun -- Cui, Xia -- Greeff, Christiaan -- Trick, Martin -- Qiu, Qi -- Cao, Xiaofeng -- Dean, Caroline -- 233039/European Research Council/International -- BB/C517633/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/G009562/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2014 Nov 27;515(7528):587-90. doi: 10.1038/nature13722. Epub 2014 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Cell &Developmental Biology, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK [2]. ; Department of Cell &Developmental Biology, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK. ; State Key Laboratory of Plant Genomics and National Center for Plant Gene Research, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences. Beijing 100101, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25219852" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arabidopsis/enzymology/*genetics ; Arabidopsis Proteins/*genetics/metabolism ; Cellular Reprogramming/genetics ; Chromosome Mapping ; DNA Methylation ; *Epigenesis, Genetic ; *Gene Expression Regulation, Plant ; Gene Silencing ; MADS Domain Proteins/*genetics ; Molecular Sequence Data ; Mutation ; Sequence Alignment ; Transcription Factors/genetics/metabolism
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  • 54
    Publication Date: 2014-12-24
    Description: Tubulin is a major component of the eukaryotic cytoskeleton, controlling cell shape, structure and dynamics, whereas its bacterial homologue FtsZ establishes the cytokinetic ring that constricts during cell division. How such different roles of tubulin and FtsZ evolved is unknown. Studying Archaea may provide clues as these organisms share characteristics with Eukarya and Bacteria. Here we report the structure and function of proteins from a distinct family related to tubulin and FtsZ, named CetZ, which co-exists with FtsZ in many archaea. CetZ X-ray crystal structures showed the FtsZ/tubulin superfamily fold, and one crystal form contained sheets of protofilaments, suggesting a structural role. However, inactivation of CetZ proteins in Haloferax volcanii did not affect cell division. Instead, CetZ1 was required for differentiation of the irregular plate-shaped cells into a rod-shaped cell type that was essential for normal swimming motility. CetZ1 formed dynamic cytoskeletal structures in vivo, relating to its capacity to remodel the cell envelope and direct rod formation. CetZ2 was also implicated in H. volcanii cell shape control. Our findings expand the known roles of the FtsZ/tubulin superfamily to include archaeal cell shape dynamics, suggesting that a cytoskeletal role might predate eukaryotic cell evolution, and they support the premise that a major function of the microbial rod shape is to facilitate swimming.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369195/" 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/PMC4369195/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Duggin, Iain G -- Aylett, Christopher H S -- Walsh, James C -- Michie, Katharine A -- Wang, Qing -- Turnbull, Lynne -- Dawson, Emma M -- Harry, Elizabeth J -- Whitchurch, Cynthia B -- Amos, Linda A -- Lowe, Jan -- MC_U105184326/Medical Research Council/United Kingdom -- U105184326/Medical Research Council/United Kingdom -- England -- Nature. 2015 Mar 19;519(7543):362-5. doi: 10.1038/nature13983. Epub 2014 Dec 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK [2] The ithree institute, University of Technology Sydney, New South Wales 2007, Australia. ; Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. ; 1] The ithree institute, University of Technology Sydney, New South Wales 2007, Australia [2] School of Physics, University of New South Wales, Sydney, New South Wales 2052, Australia. ; The ithree institute, University of Technology Sydney, New South Wales 2007, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25533961" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Archaeal Proteins/*chemistry/*metabolism ; Bacterial Proteins/chemistry/metabolism ; Cell Division ; Cell Membrane/metabolism ; *Cell Shape ; Crystallography, X-Ray ; Cytoskeletal Proteins/chemistry/metabolism ; Haloferax volcanii/*cytology/*metabolism ; Models, Molecular ; Molecular Sequence Data ; Movement ; Tubulin/chemistry/*metabolism
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  • 55
    Publication Date: 2013-11-23
    Description: Oxamniquine resistance evolved in the human blood fluke (Schistosoma mansoni) in Brazil in the 1970s. We crossed parental parasites differing ~500-fold in drug response, determined drug sensitivity and marker segregation in clonally derived second-generation progeny, and identified a single quantitative trait locus (logarithm of odds = 31) on chromosome 6. A sulfotransferase was identified as the causative gene by using RNA interference knockdown and biochemical complementation assays, and we subsequently demonstrated independent origins of loss-of-function mutations in field-derived and laboratory-selected resistant parasites. These results demonstrate the utility of linkage mapping in a human helminth parasite, while crystallographic analyses of protein-drug interactions illuminate the mode of drug action and provide a framework for rational design of oxamniquine derivatives that kill both S. mansoni and S. haematobium, the two species responsible for 〉99% of schistosomiasis cases worldwide.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136436/" 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/PMC4136436/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Valentim, Claudia L L -- Cioli, Donato -- Chevalier, Frederic D -- Cao, Xiaohang -- Taylor, Alexander B -- Holloway, Stephen P -- Pica-Mattoccia, Livia -- Guidi, Alessandra -- Basso, Annalisa -- Tsai, Isheng J -- Berriman, Matthew -- Carvalho-Queiroz, Claudia -- Almeida, Marcio -- Aguilar, Hector -- Frantz, Doug E -- Hart, P John -- LoVerde, Philip T -- Anderson, Timothy J C -- 098051/Wellcome Trust/United Kingdom -- 5R21-AI072704/AI/NIAID NIH HHS/ -- 5R21-AI096277/AI/NIAID NIH HHS/ -- C06 RR013556/RR/NCRR NIH HHS/ -- HHSN272201000005I/PHS HHS/ -- R01 AI097576/AI/NIAID NIH HHS/ -- R01-AI097576/AI/NIAID NIH HHS/ -- R21 AI072704/AI/NIAID NIH HHS/ -- R21 AI096277/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2013 Dec 13;342(6164):1385-9. doi: 10.1126/science.1243106. Epub 2013 Nov 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Biochemistry and Pathology, University of Texas Health Science Center, San Antonio, TX 78229, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24263136" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Drug Resistance/*genetics ; Gene Knockdown Techniques ; Genetic Linkage ; Helminth Proteins/*genetics ; Humans ; Molecular Sequence Data ; Mutation ; Oxamniquine/*pharmacology ; Phylogeny ; Protein Conformation ; Quantitative Trait Loci ; RNA Interference ; Schistosoma mansoni/*drug effects/*genetics ; Schistosomicides/*pharmacology ; Sulfotransferases/chemistry/classification/*genetics
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  • 56
    Publication Date: 2013-06-08
    Description: Evolutionarily young genes that serve essential functions represent a paradox; they must perform a function that either was not required until after their birth or was redundant with another gene. How young genes rapidly acquire essential function is largely unknown. We traced the evolutionary steps by which the Drosophila gene Umbrea acquired an essential role in chromosome segregation in D. melanogaster since the gene's origin less than 15 million years ago. Umbrea neofunctionalization occurred via loss of an ancestral heterochromatin-localizing domain, followed by alterations that rewired its protein interaction network and led to species-specific centromere localization. Our evolutionary cell biology approach provides temporal and mechanistic detail about how young genes gain essential function. Such innovations may constantly alter the repertoire of centromeric proteins in eukaryotes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119826/" 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/PMC4119826/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ross, Benjamin D -- Rosin, Leah -- Thomae, Andreas W -- Hiatt, Mary Alice -- Vermaak, Danielle -- de la Cruz, Aida Flor A -- Imhof, Axel -- Mellone, Barbara G -- Malik, Harmit S -- R01 GM074108/GM/NIGMS NIH HHS/ -- R01GM074108/GM/NIGMS NIH HHS/ -- T32HG000035/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Jun 7;340(6137):1211-4. doi: 10.1126/science.1234393.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23744945" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Centromere/genetics/*physiology ; Chromosomal Proteins, Non-Histone/*genetics ; Drosophila/*genetics ; Drosophila Proteins/*genetics ; *Evolution, Molecular ; Gene Duplication ; Genes, Insect/*physiology ; Molecular Sequence Data
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  • 57
    Publication Date: 2013-07-28
    Description: The essential bacterial protein FtsZ is a guanosine triphosphatase that self-assembles into a structure at the division site termed the "Z ring". During cytokinesis, the Z ring exerts a constrictive force on the membrane by using the chemical energy of guanosine triphosphate hydrolysis. However, the structural basis of this constriction remains unresolved. Here, we present the crystal structure of a guanosine diphosphate-bound Mycobacterium tuberculosis FtsZ protofilament, which exhibits a curved conformational state. The structure reveals a longitudinal interface that is important for function. The protofilament curvature highlights a hydrolysis-dependent conformational switch at the T3 loop that leads to longitudinal bending between subunits, which could generate sufficient force to drive cytokinesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816583/" 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/PMC3816583/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Ying -- Hsin, Jen -- Zhao, Lingyun -- Cheng, Yiwen -- Shang, Weina -- Huang, Kerwyn Casey -- Wang, Hong-Wei -- Ye, Sheng -- 1F32GM100677-01A1/GM/NIGMS NIH HHS/ -- DP2 OD006466/OD/NIH HHS/ -- DP2OD006466/OD/NIH HHS/ -- F32 GM100677/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Jul 26;341(6144):392-5. doi: 10.1126/science.1239248.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Life Sciences Institute, Zhejiang University, Hangzhou, 310058 Zhejiang, P.R. China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23888039" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Bacterial Proteins/*chemistry/genetics/*metabolism ; Cell Membrane/physiology ; Crystallography, X-Ray ; *Cytokinesis ; Cytoskeletal Proteins/*chemistry/genetics/*metabolism ; Escherichia coli/chemistry ; Guanosine Diphosphate/chemistry/metabolism ; Guanosine Triphosphate/metabolism ; Hydrolysis ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Molecular Dynamics Simulation ; Molecular Sequence Data ; Mycobacterium tuberculosis/*chemistry/physiology ; Point Mutation ; Protein Conformation ; Protein Multimerization ; Protein Subunits/chemistry/metabolism ; Staphylococcus aureus/chemistry
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  • 58
    Publication Date: 2013-10-26
    Description: Painful venoms are used to deter predators. Pain itself, however, can signal damage and thus serves an important adaptive function. Evolution to reduce general pain responses, although valuable for preying on venomous species, is rare, likely because it comes with the risk of reduced response to tissue damage. Bark scorpions capitalize on the protective pain pathway of predators by inflicting intensely painful stings. However, grasshopper mice regularly attack and consume bark scorpions, grooming only briefly when stung. Bark scorpion venom induces pain in many mammals (house mice, rats, humans) by activating the voltage-gated Na(+) channel Nav1.7, but has no effect on Nav1.8. Grasshopper mice Nav1.8 has amino acid variants that bind bark scorpion toxins and inhibit Na(+) currents, blocking action potential propagation and inducing analgesia. Thus, grasshopper mice have solved the predator-pain problem by using a toxin bound to a nontarget channel to block transmission of the pain signals the venom itself is initiating.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172297/" 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/PMC4172297/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rowe, Ashlee H -- Xiao, Yucheng -- Rowe, Matthew P -- Cummins, Theodore R -- Zakon, Harold H -- NS 053422/NS/NINDS NIH HHS/ -- R01 NS053422/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2013 Oct 25;342(6157):441-6. doi: 10.1126/science.1236451.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section of Neurobiology, The University of Texas at Austin, Austin, TX 78712, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24159039" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials/drug effects/physiology ; Amino Acid Sequence ; Animals ; Arvicolinae/*metabolism ; *Food Chain ; Formaldehyde/pharmacology ; Mice ; Molecular Sequence Data ; NAV1.7 Voltage-Gated Sodium Channel/chemistry/genetics/*metabolism ; NAV1.8 Voltage-Gated Sodium Channel/chemistry/genetics/*metabolism ; Pain/chemically induced/*metabolism ; *Predatory Behavior ; Protein Structure, Tertiary ; Scorpion Venoms
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  • 59
    Publication Date: 2013-03-23
    Description: Glycosylated alpha-dystroglycan (alpha-DG) serves as cellular entry receptor for multiple pathogens, and defects in its glycosylation cause hereditary Walker-Warburg syndrome (WWS). At least eight proteins are critical to glycosylate alpha-DG, but many genes mutated in WWS remain unknown. To identify modifiers of alpha-DG, we performed a haploid screen for Lassa virus entry, a hemorrhagic fever virus causing thousands of deaths annually that hijacks glycosylated alpha-DG to enter cells. In complementary screens, we profiled cells for absence of alpha-DG carbohydrate chains or biochemically related glycans. This revealed virus host factors and a suite of glycosylation units, including all known Walker-Warburg genes and five additional factors critical for the modification of alpha-DG. Our findings accentuate the complexity of this posttranslational feature and point out genes defective in dystroglycanopathies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919138/" 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/PMC3919138/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jae, Lucas T -- Raaben, Matthijs -- Riemersma, Moniek -- van Beusekom, Ellen -- Blomen, Vincent A -- Velds, Arno -- Kerkhoven, Ron M -- Carette, Jan E -- Topaloglu, Haluk -- Meinecke, Peter -- Wessels, Marja W -- Lefeber, Dirk J -- Whelan, Sean P -- van Bokhoven, Hans -- Brummelkamp, Thijn R -- AI057159/AI/NIAID NIH HHS/ -- AI081842/AI/NIAID NIH HHS/ -- R01 AI081842/AI/NIAID NIH HHS/ -- U54 AI057159/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2013 Apr 26;340(6131):479-83. doi: 10.1126/science.1233675. Epub 2013 Mar 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23519211" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cell Line ; Dystroglycans/*metabolism ; Female ; Glycosylation ; Haploidy ; Host-Pathogen Interactions/*genetics ; Humans ; Infant ; Lassa Fever/*genetics/virology ; Lassa virus/*physiology ; Male ; Membrane Proteins/*genetics ; Molecular Sequence Data ; Mutation ; Pedigree ; Proteome/*metabolism ; *Virus Internalization ; Walker-Warburg Syndrome/*genetics
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  • 60
    Publication Date: 2013-07-03
    Description: Wheat stem rust, caused by Puccinia graminis f. sp. tritici (Pgt), is a devastating disease that can cause severe yield losses. A previously uncharacterized Pgt race, designated Ug99, has overcome most of the widely used resistance genes and is threatening major wheat production areas. Here, we demonstrate that the Sr35 gene from Triticum monococcum is a coiled-coil, nucleotide-binding, leucine-rich repeat gene that confers near immunity to Ug99 and related races. This gene is absent in the A-genome diploid donor and in polyploid wheat but is effective when transferred from T. monococcum to polyploid wheat. The cloning of Sr35 opens the door to the use of biotechnological approaches to control this devastating disease and to analyses of the molecular interactions that define the wheat-rust pathosystem.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748951/" 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/PMC4748951/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Saintenac, Cyrille -- Zhang, Wenjun -- Salcedo, Andres -- Rouse, Matthew N -- Trick, Harold N -- Akhunov, Eduard -- Dubcovsky, Jorge -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Aug 16;341(6147):783-6. doi: 10.1126/science.1239022. Epub 2013 Jun 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Plant Pathology, Kansas State University, Manhattan, KS 66506, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23811222" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing ; Amino Acid Sequence ; *Basidiomycota/pathogenicity ; Cloning, Molecular ; Disease Resistance/genetics ; *Genes, Plant ; Haplotypes ; Molecular Sequence Annotation ; Molecular Sequence Data ; Mutation ; Phylogeny ; Plant Diseases/genetics/*immunology/microbiology ; Plant Proteins/chemistry/genetics ; Plant Stems/microbiology ; Plants, Genetically Modified ; Polymorphism, Single Nucleotide ; Polyploidy ; Sequence Analysis, DNA ; Triticum/*genetics/immunology/microbiology
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  • 61
    Publication Date: 2013-04-06
    Description: A variant upstream of human leukocyte antigen C (HLA-C) shows the most significant genome-wide effect on HIV control in European Americans and is also associated with the level of HLA-C expression. We characterized the differential cell surface expression levels of all common HLA-C allotypes and tested directly for effects of HLA-C expression on outcomes of HIV infection in 5243 individuals. Increasing HLA-C expression was associated with protection against multiple outcomes independently of individual HLA allelic effects in both African and European Americans, regardless of their distinct HLA-C frequencies and linkage relationships with HLA-B and HLA-A. Higher HLA-C expression was correlated with increased likelihood of cytotoxic T lymphocyte responses and frequency of viral escape mutation. In contrast, high HLA-C expression had a deleterious effect in Crohn's disease, suggesting a broader influence of HLA expression levels in human disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784322/" 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/PMC3784322/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Apps, Richard -- Qi, Ying -- Carlson, Jonathan M -- Chen, Haoyan -- Gao, Xiaojiang -- Thomas, Rasmi -- Yuki, Yuko -- Del Prete, Greg Q -- Goulder, Philip -- Brumme, Zabrina L -- Brumme, Chanson J -- John, Mina -- Mallal, Simon -- Nelson, George -- Bosch, Ronald -- Heckerman, David -- Stein, Judy L -- Soderberg, Kelly A -- Moody, M Anthony -- Denny, Thomas N -- Zeng, Xue -- Fang, Jingyuan -- Moffett, Ashley -- Lifson, Jeffrey D -- Goedert, James J -- Buchbinder, Susan -- Kirk, Gregory D -- Fellay, Jacques -- McLaren, Paul -- Deeks, Steven G -- Pereyra, Florencia -- Walker, Bruce -- Michael, Nelson L -- Weintrob, Amy -- Wolinsky, Steven -- Liao, Wilson -- Carrington, Mary -- 5-M01-RR-00722/RR/NCRR NIH HHS/ -- HHSN261200800001E/CA/NCI NIH HHS/ -- HHSN261200800001E/PHS HHS/ -- K08 AR057763/AR/NIAMS NIH HHS/ -- K08AR057763/AR/NIAMS NIH HHS/ -- K24 AI069994/AI/NIAID NIH HHS/ -- K24AI069994/AI/NIAID NIH HHS/ -- N02-CP-55504/CP/NCI NIH HHS/ -- P30 AI027763/AI/NIAID NIH HHS/ -- P30 AI027767/AI/NIAID NIH HHS/ -- P30 AI027767-24/AI/NIAID NIH HHS/ -- P30 MH62246/MH/NIMH NIH HHS/ -- PG/09/077/27964/British Heart Foundation/United Kingdom -- R01 AI046995/AI/NIAID NIH HHS/ -- R01 AI060460/AI/NIAID NIH HHS/ -- R01 AI087145/AI/NIAID NIH HHS/ -- R01 AR065174/AR/NIAMS NIH HHS/ -- R01-AI046995/AI/NIAID NIH HHS/ -- R01-AI060460/AI/NIAID NIH HHS/ -- R01-DA-04334/DA/NIDA NIH HHS/ -- R01-DA-12568/DA/NIDA NIH HHS/ -- R01-DA04334/DA/NIDA NIH HHS/ -- R01-DA12568/DA/NIDA NIH HHS/ -- R24 AI067039/AI/NIAID NIH HHS/ -- U01-AI-067854/AI/NIAID NIH HHS/ -- U01-AI-35039/AI/NIAID NIH HHS/ -- U01-AI-35040/AI/NIAID NIH HHS/ -- U01-AI-35041/AI/NIAID NIH HHS/ -- U01-AI-35042/AI/NIAID NIH HHS/ -- U01-AI-35043/AI/NIAID NIH HHS/ -- U01-AI-37613/AI/NIAID NIH HHS/ -- U01-AI-37984/AI/NIAID NIH HHS/ -- UL1 RR024131/RR/NCRR NIH HHS/ -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2013 Apr 5;340(6128):87-91. doi: 10.1126/science.1232685.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer and Inflammation Program, Laboratory of Experimental Immunology, Science Applications International Corporation-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23559252" target="_blank"〉PubMed〈/a〉
    Keywords: African Americans/genetics ; Alleles ; Amino Acid Sequence ; Anti-Retroviral Agents/therapeutic use ; Crohn Disease/genetics/immunology ; *Gene Expression Regulation ; HIV/genetics/*immunology ; HIV Infections/drug therapy/*genetics/*immunology ; HLA-C Antigens/*genetics ; Humans ; Immunodominant Epitopes/genetics ; Molecular Sequence Data ; Mutation ; Peptide Fragments/immunology ; Polymorphism, Single Nucleotide ; T-Lymphocytes, Cytotoxic/*immunology ; Viral Load/genetics
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  • 62
    Publication Date: 2013-02-02
    Description: The geographic origins of breeds and the genetic basis of variation within the widely distributed and phenotypically diverse domestic rock pigeon (Columba livia) remain largely unknown. We generated a rock pigeon reference genome and additional genome sequences representing domestic and feral populations. We found evidence for the origins of major breed groups in the Middle East and contributions from a racing breed to North American feral populations. We identified the gene EphB2 as a strong candidate for the derived head crest phenotype shared by numerous breeds, an important trait in mate selection in many avian species. We also found evidence that this trait evolved just once and spread throughout the species, and that the crest originates early in development by the localized molecular reversal of feather bud polarity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778192/" 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/PMC3778192/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shapiro, Michael D -- Kronenberg, Zev -- Li, Cai -- Domyan, Eric T -- Pan, Hailin -- Campbell, Michael -- Tan, Hao -- Huff, Chad D -- Hu, Haofu -- Vickrey, Anna I -- Nielsen, Sandra C A -- Stringham, Sydney A -- Hu, Hao -- Willerslev, Eske -- Gilbert, M Thomas P -- Yandell, Mark -- Zhang, Guojie -- Wang, Jun -- GO RC2HG005619/HG/NHGRI NIH HHS/ -- R01 GM104390/GM/NIGMS NIH HHS/ -- R01 HG004694/HG/NHGRI NIH HHS/ -- R01HG004694/HG/NHGRI NIH HHS/ -- R44 HG006579/HG/NHGRI NIH HHS/ -- RC2 HG005619/HG/NHGRI NIH HHS/ -- T32 GM007464/GM/NIGMS NIH HHS/ -- T32 HD007491/HD/NICHD NIH HHS/ -- T32GM007464/GM/NIGMS NIH HHS/ -- T32HD07491/HD/NICHD NIH HHS/ -- New York, N.Y. -- Science. 2013 Mar 1;339(6123):1063-7. doi: 10.1126/science.1230422. Epub 2013 Jan 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, University of Utah, Salt Lake City, UT 84112, USA. mike.shapiro@utah.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23371554" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Animals, Domestic/anatomy & histology/classification/genetics ; Animals, Wild/anatomy & histology/classification/genetics ; Breeding ; Columbidae/anatomy & histology/*classification/*genetics ; *Evolution, Molecular ; Feathers/anatomy & histology ; *Genetic Variation ; Genome ; Head/*anatomy & histology ; Models, Genetic ; Molecular Sequence Data ; Phylogeny ; Polymorphism, Single Nucleotide ; *Quantitative Trait, Heritable ; Receptor, EphB2/genetics ; Sequence Analysis, DNA
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  • 63
    Publication Date: 2013-04-27
    Description: Senescent and damaged mitochondria undergo selective mitophagic elimination through mechanisms requiring two Parkinson's disease factors, the mitochondrial kinase PINK1 (PTEN-induced putative kinase protein 1; PTEN is phosphatase and tensin homolog) and the cytosolic ubiquitin ligase Parkin. The nature of the PINK-Parkin interaction and the identity of key factors directing Parkin to damaged mitochondria are unknown. We show that the mitochondrial outer membrane guanosine triphosphatase mitofusin (Mfn) 2 mediates Parkin recruitment to damaged mitochondria. Parkin bound to Mfn2 in a PINK1-dependent manner; PINK1 phosphorylated Mfn2 and promoted its Parkin-mediated ubiqitination. Ablation of Mfn2 in mouse cardiac myocytes prevented depolarization-induced translocation of Parkin to the mitochondria and suppressed mitophagy. Accumulation of morphologically and functionally abnormal mitochondria induced respiratory dysfunction in Mfn2-deficient mouse embryonic fibroblasts and cardiomyocytes and in Parkin-deficient Drosophila heart tubes, causing dilated cardiomyopathy. Thus, Mfn2 functions as a mitochondrial receptor for Parkin and is required for quality control of cardiac mitochondria.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774525/" 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/PMC3774525/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Yun -- Dorn, Gerald W 2nd -- R01 HL059888/HL/NHLBI NIH HHS/ -- R21 HL107276/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2013 Apr 26;340(6131):471-5. doi: 10.1126/science.1231031.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23620051" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Autophagy ; Cardiomyopathies/enzymology ; Drosophila melanogaster ; Fibroblasts/ultrastructure ; GTP Phosphohydrolases/genetics/*metabolism ; HEK293 Cells ; Humans ; Mice ; Mice, Mutant Strains ; Mitochondria/enzymology ; Mitochondria, Heart/*enzymology ; Molecular Sequence Data ; Myocytes, Cardiac/*enzymology/ultrastructure ; Phosphorylation ; Protein Kinases/*metabolism ; Ubiquitin-Protein Ligases/*metabolism ; Ubiquitination
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  • 64
    Publication Date: 2013-10-05
    Description: Most models of gene duplication assume that the ancestral functions of the preduplication gene are independent and can therefore be neatly partitioned between descendant paralogs. However, many gene products, such as transcriptional regulators, are components within cooperative assemblies; here, we show that a natural consequence of duplication and divergence of such proteins can be competitive interference between the paralogs. Our example is based on the duplication of the essential MADS-box transcriptional regulator Mcm1, which is found in all fungi and regulates a large set of genes. We show that a set of historical amino acid sequence substitutions minimized paralog interference in contemporary species and, in doing so, increased the molecular complexity of this gene regulatory network. We propose that paralog interference is a common constraint on gene duplicate evolution, and its resolution, which can generate additional regulatory complexity, is needed to stabilize duplicated genes in the genome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3911913/" 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/PMC3911913/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baker, Christopher R -- Hanson-Smith, Victor -- Johnson, Alexander D -- F32 GM108299/GM/NIGMS NIH HHS/ -- R01 GM037049/GM/NIGMS NIH HHS/ -- R01 GM057049/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Oct 4;342(6154):104-8. doi: 10.1126/science.1240810.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology and Microbiology, University of California, San Francisco, CA 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24092741" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arginine/genetics ; Candida albicans/genetics ; *Evolution, Molecular ; *Gene Duplication ; *Gene Regulatory Networks ; Kluyveromyces/genetics ; Minichromosome Maintenance 1 Protein/*genetics ; Molecular Sequence Data ; Saccharomyces cerevisiae/genetics ; Sequence Deletion ; *Transcription, Genetic
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  • 65
    Publication Date: 2013-03-23
    Description: Serotonin or 5-hydroxytryptamine (5-HT) regulates a wide spectrum of human physiology through the 5-HT receptor family. We report the crystal structures of the human 5-HT1B G protein-coupled receptor bound to the agonist antimigraine medications ergotamine and dihydroergotamine. The structures reveal similar binding modes for these ligands, which occupy the orthosteric pocket and an extended binding pocket close to the extracellular loops. The orthosteric pocket is formed by residues conserved in the 5-HT receptor family, clarifying the family-wide agonist activity of 5-HT. Compared with the structure of the 5-HT2B receptor, the 5-HT1B receptor displays a 3 angstrom outward shift at the extracellular end of helix V, resulting in a more open extended pocket that explains subtype selectivity. Together with docking and mutagenesis studies, these structures provide a comprehensive structural basis for understanding receptor-ligand interactions and designing subtype-selective serotonergic drugs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644373/" 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/PMC3644373/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Chong -- Jiang, Yi -- Ma, Jinming -- Wu, Huixian -- Wacker, Daniel -- Katritch, Vsevolod -- Han, Gye Won -- Liu, Wei -- Huang, Xi-Ping -- Vardy, Eyal -- McCorvy, John D -- Gao, Xiang -- Zhou, X Edward -- Melcher, Karsten -- Zhang, Chenghai -- Bai, Fang -- Yang, Huaiyu -- Yang, Linlin -- Jiang, Hualiang -- Roth, Bryan L -- Cherezov, Vadim -- Stevens, Raymond C -- Xu, H Eric -- P50 GM073197/GM/NIGMS NIH HHS/ -- R01 DA027170/DA/NIDA NIH HHS/ -- R01 DA27170/DA/NIDA NIH HHS/ -- R01 DK071662/DK/NIDDK NIH HHS/ -- R01 MH061887/MH/NIMH NIH HHS/ -- R01 MH61887/MH/NIMH NIH HHS/ -- U19 MH082441/MH/NIMH NIH HHS/ -- U19 MH82441/MH/NIMH NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 May 3;340(6132):610-4. doi: 10.1126/science.1232807. Epub 2013 Mar 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23519210" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding Sites ; Crystallography, X-Ray ; Dihydroergotamine/chemistry/*metabolism ; Ergotamine/chemistry/*metabolism ; Humans ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Ligands ; Lysergic Acid Diethylamide/chemistry/metabolism ; Models, Molecular ; Molecular Docking Simulation ; Molecular Sequence Data ; Mutagenesis ; Norfenfluramine/chemistry/metabolism ; Pindolol/analogs & derivatives/chemistry/metabolism ; Propranolol/chemistry/metabolism ; Protein Conformation ; Protein Folding ; Protein Structure, Secondary ; Receptor, Serotonin, 5-HT1B/*chemistry/genetics/*metabolism ; Serotonin 5-HT1 Receptor Agonists/*chemistry/*metabolism ; Tryptamines/chemistry/metabolism
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  • 66
    Publication Date: 2013-08-24
    Description: Small open reading frames (smORFs) are short DNA sequences that are able to encode small peptides of less than 100 amino acids. Study of these elements has been neglected despite thousands existing in our genomes. We and others previously showed that peptides as short as 11 amino acids are translated and provide essential functions during insect development. Here, we describe two peptides of less than 30 amino acids regulating calcium transport, and hence influencing regular muscle contraction, in the Drosophila heart. These peptides seem conserved for more than 550 million years in a range of species from flies to humans, in which they have been implicated in cardiac pathologies. Such conservation suggests that the mechanisms for heart regulation are ancient and that smORFs may be a fundamental genome component that should be studied systematically.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Magny, Emile G -- Pueyo, Jose Ignacio -- Pearl, Frances M G -- Cespedes, Miguel Angel -- Niven, Jeremy E -- Bishop, Sarah A -- Couso, Juan Pablo -- 087516/Wellcome Trust/United Kingdom -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2013 Sep 6;341(6150):1116-20. doi: 10.1126/science.1238802. Epub 2013 Aug 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex BN1 9QG, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23970561" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Calcium/*metabolism ; Conserved Sequence ; Drosophila Proteins/chemistry/genetics/metabolism/*physiology ; Drosophila melanogaster ; Evolution, Molecular ; Ion Transport ; Molecular Sequence Data ; Muscle Proteins/chemistry/genetics/*physiology ; Muscle, Skeletal/*metabolism ; *Myocardial Contraction ; Myocardium/*metabolism ; Open Reading Frames ; Peptides/chemistry/genetics/*physiology ; Protein Structure, Secondary ; Transaldolase/genetics/metabolism
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  • 67
    Publication Date: 2013-06-01
    Description: Chromosome segregation during mitosis requires assembly of the kinetochore complex at the centromere. Kinetochore assembly depends on specific recognition of the histone variant CENP-A in the centromeric nucleosome by centromere protein C (CENP-C). We have defined the determinants of this recognition mechanism and discovered that CENP-C binds a hydrophobic region in the CENP-A tail and docks onto the acidic patch of histone H2A and H2B. We further found that the more broadly conserved CENP-C motif uses the same mechanism for CENP-A nucleosome recognition. Our findings reveal a conserved mechanism for protein recruitment to centromeres and a histone recognition mode whereby a disordered peptide binds the histone tail through hydrophobic interactions facilitated by nucleosome docking.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763809/" 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/PMC3763809/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kato, Hidenori -- Jiang, Jiansheng -- Zhou, Bing-Rui -- Rozendaal, Marieke -- Feng, Hanqiao -- Ghirlando, Rodolfo -- Xiao, T Sam -- Straight, Aaron F -- Bai, Yawen -- R01 GM074728/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- ZIA AI000960-07/Intramural NIH HHS/ -- New York, N.Y. -- Science. 2013 May 31;340(6136):1110-3. doi: 10.1126/science.1235532.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, Bethesda, MD 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23723239" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Autoantigens/metabolism ; Binding Sites ; Centromere/*metabolism ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; Conserved Sequence ; Drosophila ; Histones/*metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Molecular Sequence Data ; Nucleosomes/*metabolism ; Protein Structure, Secondary
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  • 68
    Publication Date: 2013-12-18
    Description: Erythropoietin is a signaling glycoprotein that controls the fundamental process of erythropoiesis, orchestrating the production and maintenance of red blood cells. As administrated clinically, erythropoietin has a polypeptide backbone with complex dishomogeneity in its carbohydrate domains. Here we describe the total synthesis of homogeneous erythropoietin with consensus carbohydrate domains incorporated at all of the native glycosylation sites. The oligosaccharide sectors were built by total synthesis and attached stereospecifically to peptidyl fragments of the wild-type primary sequence, themselves obtained by solid-phase peptide synthesis. The glycopeptidyl constructs were joined by chemical ligation, followed by metal-free dethiylation, and subsequently folded. This homogeneous erythropoietin glycosylated at the three wild-type aspartates with N-linked high-mannose sialic acid-containing oligosaccharides and O-linked glycophorin exhibits Procrit-level in vivo activity in mice.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080428/" 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/PMC4080428/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Ping -- Dong, Suwei -- Shieh, Jae-Hung -- Peguero, Elizabeth -- Hendrickson, Ronald -- Moore, Malcolm A S -- Danishefsky, Samuel J -- HL025848/HL/NHLBI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- R01 GM109760/GM/NIGMS NIH HHS/ -- R01 HL025848/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2013 Dec 13;342(6164):1357-60. doi: 10.1126/science.1245095.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24337294" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Aspartic Acid/chemistry ; Cells, Cultured ; Consensus Sequence ; Dose-Response Relationship, Drug ; Erythrocyte Count ; Erythropoietin/*administration & dosage/*chemical synthesis/chemistry ; Glycophorin/chemistry ; Glycosylation ; Injections, Subcutaneous ; Mannose/chemistry ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; N-Acetylneuraminic Acid/chemistry ; Oligosaccharides/chemistry ; Reticulocytes/drug effects
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  • 69
    Publication Date: 2013-01-26
    Description: The human genome contains ~50 genes that were derived from transposable elements or transposons, and many are now integral components of cellular gene expression programs. The human THAP9 gene is related to the Drosophila P-element transposase. Here, we show that human THAP9 can mobilize Drosophila P-elements in both Drosophila and human cells. Chimeric proteins formed between the Drosophila P-element transposase N-terminal THAP DNA binding domain and the C-terminal regions of human THAP9 can also mobilize Drosophila P elements. Our results indicate that human THAP9 is an active DNA transposase that, although "domesticated," still retains the catalytic activity to mobilize P transposable elements across species.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779457/" 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/PMC3779457/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Majumdar, Sharmistha -- Singh, Anita -- Rio, Donald C -- R01 GM048862/GM/NIGMS NIH HHS/ -- R01 GM094890/GM/NIGMS NIH HHS/ -- R01 GM097352/GM/NIGMS NIH HHS/ -- R01 GM104385/GM/NIGMS NIH HHS/ -- R01GM094890/GM/NIGMS NIH HHS/ -- R01GM104385/GM/NIGMS NIH HHS/ -- R01GM48862/GM/NIGMS NIH HHS/ -- R01GM61987/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Jan 25;339(6118):446-8. doi: 10.1126/science.1231789.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3204, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23349291" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Cell Line ; *DNA Transposable Elements ; Drosophila/genetics ; Genome, Human ; HEK293 Cells ; Humans ; Molecular Sequence Data ; Recombinant Fusion Proteins/metabolism ; Sequence Analysis, DNA ; Transfection ; Transposases/chemistry/*genetics/*metabolism
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  • 70
    Publication Date: 2013-07-03
    Description: Wheat stem rust, caused by the fungus Puccinia graminis f. sp. tritici, afflicts bread wheat (Triticum aestivum). New virulent races collectively referred to as "Ug99" have emerged, which threaten global wheat production. The wheat gene Sr33, introgressed from the wild relative Aegilops tauschii into bread wheat, confers resistance to diverse stem rust races, including the Ug99 race group. We cloned Sr33, which encodes a coiled-coil, nucleotide-binding, leucine-rich repeat protein. Sr33 is orthologous to the barley (Hordeum vulgare) Mla mildew resistance genes that confer resistance to Blumeria graminis f. sp. hordei. The wheat Sr33 gene functions independently of RAR1, SGT1, and HSP90 chaperones. Haplotype analysis from diverse collections of Ae. tauschii placed the origin of Sr33 resistance near the southern coast of the Caspian Sea.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Periyannan, Sambasivam -- Moore, John -- Ayliffe, Michael -- Bansal, Urmil -- Wang, Xiaojing -- Huang, Li -- Deal, Karin -- Luo, Mingcheng -- Kong, Xiuying -- Bariana, Harbans -- Mago, Rohit -- McIntosh, Robert -- Dodds, Peter -- Dvorak, Jan -- Lagudah, Evans -- New York, N.Y. -- Science. 2013 Aug 16;341(6147):786-8. doi: 10.1126/science.1239028. Epub 2013 Jun 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Commonwealth Scientific and Industrial Research Organization (CSIRO) Plant Industry, Canberra, ACT 2601, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23811228" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; *Basidiomycota/pathogenicity ; Cloning, Molecular ; Disease Resistance/genetics ; *Genes, Plant ; Haplotypes ; Hordeum/genetics ; Hybridization, Genetic ; Molecular Chaperones/genetics/metabolism ; Molecular Sequence Data ; Mutation ; Plant Diseases/genetics/*immunology/microbiology ; Plant Proteins/chemistry/genetics/metabolism ; Plant Stems/microbiology ; Plants, Genetically Modified ; Poaceae/*genetics ; Synteny ; Triticum/*genetics/*microbiology
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  • 71
    Publication Date: 2013-03-23
    Description: Kinesin-mediated cargo transport is required for many cellular functions and plays a key role in pathological processes. Structural information on how kinesins recognize their cargoes is required for a molecular understanding of this fundamental and ubiquitous process. Here, we present the crystal structure of the tetratricopeptide repeat domain of kinesin light chain 2 in complex with a cargo peptide harboring a "tryptophan-acidic" motif derived from SKIP (SifA-kinesin interacting protein), a critical host determinant in Salmonella pathogenesis and a regulator of lysosomal positioning. Structural data together with biophysical, biochemical, and cellular assays allow us to propose a framework for intracellular transport based on the binding by kinesin-1 of W-acidic cargo motifs through a combination of electrostatic interactions and sequence-specific elements, providing direct molecular evidence of the mechanisms for kinesin-1:cargo recognition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693442/" 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/PMC3693442/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pernigo, Stefano -- Lamprecht, Anneri -- Steiner, Roberto A -- Dodding, Mark P -- 097316/Wellcome Trust/United Kingdom -- British Heart Foundation/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2013 Apr 19;340(6130):356-9. doi: 10.1126/science.1234264. Epub 2013 Mar 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23519214" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Bacterial Proteins/*chemistry/metabolism ; Crystallography, X-Ray ; Glycoproteins/*chemistry/metabolism ; HeLa Cells ; Humans ; Mice ; Microtubule-Associated Proteins/*chemistry/genetics/metabolism ; Molecular Sequence Data ; Mutation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Tryptophan/chemistry/genetics/metabolism
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  • 72
    Publication Date: 2013-12-07
    Description: The 2013 outbreak of avian-origin H7N9 influenza in eastern China has raised concerns about its ability to transmit in the human population. The hemagglutinin glycoprotein of most human H7N9 viruses carries Leu(226), a residue linked to adaptation of H2N2 and H3N2 pandemic viruses to human receptors. However, glycan array analysis of the H7 hemagglutinin reveals negligible binding to humanlike alpha2-6-linked receptors and strong preference for a subset of avian-like alpha2-3-linked glycans recognized by all avian H7 viruses. Crystal structures of H7N9 hemagglutinin and six hemagglutinin-glycan complexes have elucidated the structural basis for preferential recognition of avian-like receptors. These findings suggest that the current human H7N9 viruses are poorly adapted for efficient human-to-human transmission.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954636/" 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/PMC3954636/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Rui -- de Vries, Robert P -- Zhu, Xueyong -- Nycholat, Corwin M -- McBride, Ryan -- Yu, Wenli -- Paulson, James C -- Wilson, Ian A -- GM62116/GM/NIGMS NIH HHS/ -- P41GM103393/GM/NIGMS NIH HHS/ -- P41RR001209/RR/NCRR NIH HHS/ -- R56 AI099275/AI/NIAID NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Dec 6;342(6163):1230-5. doi: 10.1126/science.1243761.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24311689" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Binding Sites ; Birds ; Carbohydrate Conformation ; Crystallography, X-Ray ; Hemagglutinin Glycoproteins, Influenza Virus/*chemistry/*metabolism ; Humans ; Influenza A Virus, H7N9 Subtype/*metabolism/*pathogenicity ; Influenza in Birds/transmission/virology ; Influenza, Human/transmission/virology ; Ligands ; Microarray Analysis ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Polysaccharides/chemistry/*metabolism ; Receptors, Virus/chemistry/*metabolism ; Recombinant Proteins/chemistry/metabolism
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  • 73
    Publication Date: 2013-06-08
    Description: Repulsive guidance molecule family members (RGMs) control fundamental and diverse cellular processes, including motility and adhesion, immune cell regulation, and systemic iron metabolism. However, it is not known how RGMs initiate signaling through their common cell-surface receptor, neogenin (NEO1). Here, we present crystal structures of the NEO1 RGM-binding region and its complex with human RGMB (also called dragon). The RGMB structure reveals a previously unknown protein fold and a functionally important autocatalytic cleavage mechanism and provides a framework to explain numerous disease-linked mutations in RGMs. In the complex, two RGMB ectodomains conformationally stabilize the juxtamembrane regions of two NEO1 receptors in a pH-dependent manner. We demonstrate that all RGM-NEO1 complexes share this architecture, which therefore represents the core of multiple signaling pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4730555/" 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/PMC4730555/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bell, Christian H -- Healey, Eleanor -- van Erp, Susan -- Bishop, Benjamin -- Tang, Chenxiang -- Gilbert, Robert J C -- Aricescu, A Radu -- Pasterkamp, R Jeroen -- Siebold, Christian -- 082301/Wellcome Trust/United Kingdom -- 083111/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 097301/Wellcome Trust/United Kingdom -- A14414/Cancer Research UK/United Kingdom -- G0700232/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2013 Jul 5;341(6141):77-80. doi: 10.1126/science.1232322. Epub 2013 Jun 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. christian@strubi.ox.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23744777" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Biophysical Phenomena ; Cell Adhesion Molecules, Neuronal/*chemistry/genetics ; Conserved Sequence ; Crystallography, X-Ray ; Humans ; Membrane Proteins/*chemistry ; Mutation ; Oligopeptides/chemistry ; Protein Structure, Tertiary ; Signal Transduction
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  • 74
    Publication Date: 2013-06-08
    Description: Phosphatase and tensin homolog on chromosome ten (PTEN) is a tumor suppressor and an antagonist of the phosphoinositide-3 kinase (PI3K) pathway. We identified a 576-amino acid translational variant of PTEN, termed PTEN-Long, that arises from an alternative translation start site 519 base pairs upstream of the ATG initiation sequence, adding 173 N-terminal amino acids to the normal PTEN open reading frame. PTEN-Long is a membrane-permeable lipid phosphatase that is secreted from cells and can enter other cells. As an exogenous agent, PTEN-Long antagonized PI3K signaling and induced tumor cell death in vitro and in vivo. By providing a means to restore a functional tumor-suppressor protein to tumor cells, PTEN-Long may have therapeutic uses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935617/" 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/PMC3935617/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hopkins, Benjamin D -- Fine, Barry -- Steinbach, Nicole -- Dendy, Meaghan -- Rapp, Zachary -- Shaw, Jacquelyn -- Pappas, Kyrie -- Yu, Jennifer S -- Hodakoski, Cindy -- Mense, Sarah -- Klein, Joshua -- Pegno, Sarah -- Sulis, Maria-Luisa -- Goldstein, Hannah -- Amendolara, Benjamin -- Lei, Liang -- Maurer, Matthew -- Bruce, Jeffrey -- Canoll, Peter -- Hibshoosh, Hanina -- Parsons, Ramon -- 2T32 CA09503/CA/NCI NIH HHS/ -- CA082783/CA/NCI NIH HHS/ -- CA097403/CA/NCI NIH HHS/ -- P01 CA097403/CA/NCI NIH HHS/ -- R01 CA082783/CA/NCI NIH HHS/ -- R01 CA155117/CA/NCI NIH HHS/ -- R01 NS066955/NS/NINDS NIH HHS/ -- R01 NS073610/NS/NINDS NIH HHS/ -- R01NS066955/NS/NINDS NIH HHS/ -- T32 CA009503/CA/NCI NIH HHS/ -- T32 GM008224/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Jul 26;341(6144):399-402. doi: 10.1126/science.1234907. Epub 2013 Jun 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23744781" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Cell Line, Tumor ; *Cell Survival ; Embryonic Stem Cells ; Glioblastoma/drug therapy/metabolism/pathology ; HEK293 Cells ; Humans ; Mice ; Mice, Nude ; Molecular Sequence Data ; Mutation ; PTEN Phosphohydrolase/*chemistry/genetics/*metabolism/pharmacology ; Peptide Chain Initiation, Translational ; Phosphatidylinositol 3-Kinase/*metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Messenger/genetics/metabolism ; *Signal Transduction/drug effects ; Xenograft Model Antitumor Assays
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  • 75
    Publication Date: 2013-05-04
    Description: Superoxide and other reactive oxygen species (ROS) originate from several natural sources and profoundly influence numerous elemental cycles, including carbon and trace metals. In the deep ocean, the permanent absence of light precludes currently known ROS sources, yet ROS production mysteriously occurs. Here, we show that taxonomically and ecologically diverse heterotrophic bacteria from aquatic and terrestrial environments are a vast, unrecognized, and light-independent source of superoxide, and perhaps other ROS derived from superoxide. Superoxide production by a model bacterium within the ubiquitous Roseobacter clade involves an extracellular oxidoreductase that is stimulated by the reduced form of nicotinamide adenine dinucleotide (NADH), suggesting a surprising homology with eukaryotic organisms. The consequences of ROS cycling in immense aphotic zones representing key sites of nutrient regeneration and carbon export must now be considered, including potential control of carbon remineralization and metal bioavailability.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Diaz, Julia M -- Hansel, Colleen M -- Voelker, Bettina M -- Mendes, Chantal M -- Andeer, Peter F -- Zhang, Tong -- New York, N.Y. -- Science. 2013 Jun 7;340(6137):1223-6. doi: 10.1126/science.1237331. Epub 2013 May 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23641059" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Carbon Cycle ; *Heterotrophic Processes ; Mercury/*metabolism ; Molecular Sequence Data ; NAD/metabolism ; Oxidoreductases/metabolism ; Phylogeny ; Roseobacter/classification/*metabolism ; Superoxides/*metabolism
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  • 76
    Publication Date: 2013-03-23
    Description: Toll-like receptor 7 (TLR7) and TLR8 recognize single-stranded RNA and initiate innate immune responses. Several synthetic agonists of TLR7-TLR8 display novel therapeutic potential; however, the molecular basis for ligand recognition and activation of signaling by TLR7 or TLR8 is largely unknown. In this study, the crystal structures of unliganded and ligand-induced activated human TLR8 dimers were elucidated. Ligand recognition was mediated by a dimerization interface formed by two protomers. Upon ligand stimulation, the TLR8 dimer was reorganized such that the two C termini were brought into proximity. The loop between leucine-rich repeat 14 (LRR14) and LRR15 was cleaved; however, the N- and C-terminal halves remained associated and contributed to ligand recognition and dimerization. Thus, ligand binding induces reorganization of the TLR8 dimer, which enables downstream signaling processes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tanji, Hiromi -- Ohto, Umeharu -- Shibata, Takuma -- Miyake, Kensuke -- Shimizu, Toshiyuki -- New York, N.Y. -- Science. 2013 Mar 22;339(6126):1426-9. doi: 10.1126/science.1229159.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23520111" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Crystallography, X-Ray ; Humans ; Hydrogen Bonding ; Imidazoles/chemistry/*metabolism ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Mutant Proteins/chemistry/metabolism ; Protein Binding ; Protein Conformation ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Quinolines/chemistry/*metabolism ; Signal Transduction ; Thiazoles/chemistry/*metabolism ; Toll-Like Receptor 8/*agonists/*chemistry/metabolism
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  • 77
    Publication Date: 2013-05-11
    Description: Differences in biomolecular sequence and function underlie dramatic ranges of appearance and behavior among species. We studied the basic region-leucine zipper (bZIP) transcription factors and quantified bZIP dimerization networks for five metazoan and two single-cell species, measuring interactions in vitro for 2891 protein pairs. Metazoans have a higher proportion of heteromeric bZIP interactions and more network complexity than the single-cell species. The metazoan bZIP interactomes have broadly similar structures, but there has been extensive rewiring of connections compared to the last common ancestor, and each species network is highly distinct. Many metazoan bZIP orthologs and paralogs have strikingly different interaction specificities, and some differences arise from minor sequence changes. Our data show that a shifting landscape of biochemical functions related to signaling and gene expression contributes to species diversity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115154/" 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/PMC4115154/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reinke, Aaron W -- Baek, Jiyeon -- Ashenberg, Orr -- Keating, Amy E -- GM067681/GM/NIGMS NIH HHS/ -- R01 GM067681/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 May 10;340(6133):730-4. doi: 10.1126/science.1233465.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massachusetts Institute of Technology, Department of Biology, Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23661758" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Basic-Leucine Zipper Transcription Factors/chemistry/genetics/*metabolism ; Conserved Sequence ; *Evolution, Molecular ; Humans ; *Metabolic Networks and Pathways ; Molecular Sequence Data ; Protein Multimerization
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  • 78
    Publication Date: 2013-03-09
    Description: A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1alpha and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu(230), located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799917/" 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/PMC3799917/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hubbard, Basil P -- Gomes, Ana P -- Dai, Han -- Li, Jun -- Case, April W -- Considine, Thomas -- Riera, Thomas V -- Lee, Jessica E -- E, Sook Yen -- Lamming, Dudley W -- Pentelute, Bradley L -- Schuman, Eli R -- Stevens, Linda A -- Ling, Alvin J Y -- Armour, Sean M -- Michan, Shaday -- Zhao, Huizhen -- Jiang, Yong -- Sweitzer, Sharon M -- Blum, Charles A -- Disch, Jeremy S -- Ng, Pui Yee -- Howitz, Konrad T -- Rolo, Anabela P -- Hamuro, Yoshitomo -- Moss, Joel -- Perni, Robert B -- Ellis, James L -- Vlasuk, George P -- Sinclair, David A -- P01 AG027916/AG/NIA NIH HHS/ -- R01 AG019719/AG/NIA NIH HHS/ -- R01 AG028730/AG/NIA NIH HHS/ -- R37 AG028730/AG/NIA NIH HHS/ -- ZIA HL000659-20/Intramural NIH HHS/ -- New York, N.Y. -- Science. 2013 Mar 8;339(6124):1216-9. doi: 10.1126/science.1231097.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23471411" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Amino Acid Motifs ; Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Cells, Cultured ; Enzyme Activation ; Forkhead Transcription Factors/chemistry/genetics ; Glutamic Acid/chemistry/genetics ; Heterocyclic Compounds with 4 or More Rings/chemistry/pharmacology ; Humans ; Hydrophobic and Hydrophilic Interactions ; Mice ; Molecular Sequence Data ; Myoblasts/drug effects/enzymology ; Protein Structure, Tertiary ; Sirtuin 1/*chemistry/genetics/*metabolism ; Stilbenes/chemistry/*pharmacology ; Substrate Specificity
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  • 79
    Publication Date: 2013-03-30
    Description: Posttranslational lipidation provides critical modulation of the functions of some proteins. Isoprenoids (i.e., farnesyl or geranylgeranyl groups) are attached to cysteine residues in proteins containing C-terminal CAAX sequence motifs (where A is an aliphatic residue and X is any residue). Isoprenylation is followed by cleavage of the AAX amino acid residues and, in some cases, by additional proteolytic cuts. We determined the crystal structure of the CAAX protease Ste24p, a zinc metalloprotease catalyzing two proteolytic steps in the maturation of yeast mating pheromone a-factor. The Ste24p core structure is a ring of seven transmembrane helices enclosing a voluminous cavity containing the active site and substrate-binding groove. The cavity is accessible to the external milieu by means of gaps between splayed transmembrane helices. We hypothesize that cleavage proceeds by means of a processive mechanism of substrate insertion, translocation, and ejection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136949/" 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/PMC4136949/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pryor, Edward E Jr -- Horanyi, Peter S -- Clark, Kathleen M -- Fedoriw, Nadia -- Connelly, Sara M -- Koszelak-Rosenblum, Mary -- Zhu, Guangyu -- Malkowski, Michael G -- Wiener, Michael C -- Dumont, Mark E -- P30 CA044579/CA/NCI NIH HHS/ -- U54 GM094611/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Mar 29;339(6127):1600-4. doi: 10.1126/science.1232048.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Membrane Protein Structural Biology Consortium, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23539602" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Catalytic Domain ; Cell Membrane/*enzymology ; Crystallography, X-Ray ; Membrane Proteins/*chemistry ; Metalloendopeptidases/*chemistry ; Molecular Sequence Data ; Protein Structure, Secondary ; Saccharomyces cerevisiae Proteins/*chemistry ; Substrate Specificity
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  • 80
    Publication Date: 2013-03-30
    Description: Mutations in the nuclear membrane zinc metalloprotease ZMPSTE24 lead to diseases of lamin processing (laminopathies), such as the premature aging disease progeria and metabolic disorders. ZMPSTE24 processes prelamin A, a component of the nuclear lamina intermediate filaments, by cleaving it at two sites. Failure of this processing results in accumulation of farnesylated, membrane-associated prelamin A. The 3.4 angstrom crystal structure of human ZMPSTE24 has a seven transmembrane alpha-helical barrel structure, surrounding a large, water-filled, intramembrane chamber, capped by a zinc metalloprotease domain with the catalytic site facing into the chamber. The 3.8 angstrom structure of a complex with a CSIM tetrapeptide showed that the mode of binding of the substrate resembles that of an insect metalloprotease inhibitor in thermolysin. Laminopathy-associated mutations predicted to reduce ZMPSTE24 activity map to the zinc metalloprotease peptide-binding site and to the bottom of the chamber.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Quigley, Andrew -- Dong, Yin Yao -- Pike, Ashley C W -- Dong, Liang -- Shrestha, Leela -- Berridge, Georgina -- Stansfeld, Phillip J -- Sansom, Mark S P -- Edwards, Aled M -- Bountra, Chas -- von Delft, Frank -- Bullock, Alex N -- Burgess-Brown, Nicola A -- Carpenter, Elisabeth P -- 092809/Wellcome Trust/United Kingdom -- Canadian Institutes of Health Research/Canada -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2013 Mar 29;339(6127):1604-7. doi: 10.1126/science.1231513.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Genomics Consortium, University of Oxford, Oxford, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23539603" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Catalytic Domain ; Crystallography, X-Ray ; Humans ; Lamin Type A ; Membrane Proteins/*chemistry/genetics ; Metabolism, Inborn Errors/genetics/*metabolism ; Metalloendopeptidases/*chemistry/genetics ; Molecular Sequence Data ; Nuclear Proteins/chemistry/genetics/*metabolism ; Progeria/genetics/metabolism ; Protein Conformation ; Protein Precursors/chemistry/genetics/*metabolism ; Substrate Specificity ; Thermolysin/chemistry
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  • 81
    Publication Date: 2013-08-03
    Description: The posttranslational modification of proteins and their regulation by metabolites represent conserved mechanisms in biology. At the confluence of these two processes, we report that the primary glycolytic intermediate 1,3-bisphosphoglycerate (1,3-BPG) reacts with select lysine residues in proteins to form 3-phosphoglyceryl-lysine (pgK). This reaction, which does not require enzyme catalysis, but rather exploits the electrophilicity of 1,3-BPG, was found by proteomic profiling to be enriched on diverse classes of proteins and prominently in or around the active sites of glycolytic enzymes. pgK modifications inhibit glycolytic enzymes and, in cells exposed to high glucose, accumulate on these enzymes to create a potential feedback mechanism that contributes to the buildup and redirection of glycolytic intermediates to alternate biosynthetic pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005992/" 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/PMC4005992/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moellering, Raymond E -- Cravatt, Benjamin F -- CA087660/CA/NCI NIH HHS/ -- R37 CA087660/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2013 Aug 2;341(6145):549-53. doi: 10.1126/science.1238327.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA. rmoeller@scripps.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23908237" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Biomarkers, Tumor/chemistry/metabolism ; Catalysis ; Cell Line ; DNA-Binding Proteins/chemistry/metabolism ; Diphosphoglyceric Acids/*metabolism ; Glucose/metabolism ; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/chemistry/metabolism ; Glycerophosphates/*metabolism ; *Glycolysis ; Humans ; Lysine/*analogs & derivatives/*metabolism ; Mice ; Molecular Sequence Data ; Phosphopyruvate Hydratase/chemistry/metabolism ; *Protein Processing, Post-Translational ; Proteins/chemistry/*metabolism ; Tumor Suppressor Proteins/chemistry/metabolism
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  • 82
    Publication Date: 2013-05-04
    Description: In the past, avian influenza viruses have crossed species barriers to trigger human pandemics by reassorting with mammal-infective viruses in intermediate livestock hosts. H5N1 viruses are able to infect pigs, and some of them have affinity for the mammalian type alpha-2,6-linked sialic acid airway receptor. Using reverse genetics, we systematically created 127 reassortant viruses between a duck isolate of H5N1, specifically retaining its hemagglutinin (HA) gene throughout, and a highly transmissible, human-infective H1N1 virus. We tested the virulence of the reassortants in mice as a correlate for virulence in humans and tested transmissibility in guinea pigs, which have both avian and mammalian types of airway receptor. Transmission studies showed that the H1N1 virus genes encoding acidic polymerase and nonstructural protein made the H5N1 virus transmissible by respiratory droplet between guinea pigs without killing them. Further experiments implicated other H1N1 genes in the enhancement of mammal-to-mammal transmission, including those that encode nucleoprotein, neuraminidase, and matrix, as well as mutations in H5 HA that improve affinity for humanlike airway receptors. Hence, avian H5N1 subtype viruses do have the potential to acquire mammalian transmissibility by reassortment in current agricultural scenarios.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Ying -- Zhang, Qianyi -- Kong, Huihui -- Jiang, Yongping -- Gao, Yuwei -- Deng, Guohua -- Shi, Jianzhong -- Tian, Guobin -- Liu, Liling -- Liu, Jinxiong -- Guan, Yuntao -- Bu, Zhigao -- Chen, Hualan -- New York, N.Y. -- Science. 2013 Jun 21;340(6139):1459-63. doi: 10.1126/science.1229455. Epub 2013 May 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People's Republic of China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23641061" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Brain/virology ; Cell Line ; Ferrets ; Genes, Viral ; Guinea Pigs ; Hemagglutinin Glycoproteins, Influenza Virus/chemistry/genetics ; Humans ; Influenza A Virus, H1N1 Subtype/*genetics/pathogenicity ; Influenza A Virus, H5N1 Subtype/*genetics/pathogenicity ; Influenza, Human/transmission/virology ; Mice ; Mice, Inbred BALB C ; Molecular Sequence Data ; Mutation ; Orthomyxoviridae Infections/*transmission/*virology ; Reassortant Viruses/*genetics/*pathogenicity ; Receptors, Cell Surface/metabolism ; Receptors, Virus/metabolism ; Respiratory System/*virology ; Reverse Genetics ; Ribonucleoproteins/metabolism ; Viral Proteins/genetics/metabolism ; Virus Replication
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  • 83
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2013-04-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Leslie, Mitch -- New York, N.Y. -- Science. 2013 Apr 5;340(6128):27. doi: 10.1126/science.340.6128.27.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23559233" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Guanylate Kinase/*chemistry/*genetics ; Humans ; Neoplasms/enzymology ; Neurons/*enzymology ; Protein Structure, Secondary ; *Pseudogenes
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  • 84
    Publication Date: 2013-01-05
    Description: The ubiquitin system regulates virtually all aspects of cellular function. We report a method to target the myriad enzymes that govern ubiquitination of protein substrates. We used massively diverse combinatorial libraries of ubiquitin variants to develop inhibitors of four deubiquitinases (DUBs) and analyzed the DUB-inhibitor complexes with crystallography. We extended the selection strategy to the ubiquitin conjugating (E2) and ubiquitin ligase (E3) enzymes and found that ubiquitin variants can also enhance enzyme activity. Last, we showed that ubiquitin variants can bind selectively to ubiquitin-binding domains. Ubiquitin variants exhibit selective function in cells and thus enable orthogonal modulation of specific enzymatic steps in the ubiquitin system.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815447/" 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/PMC3815447/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ernst, Andreas -- Avvakumov, George -- Tong, Jiefei -- Fan, Yihui -- Zhao, Yanling -- Alberts, Philipp -- Persaud, Avinash -- Walker, John R -- Neculai, Ana-Mirela -- Neculai, Dante -- Vorobyov, Andrew -- Garg, Pankaj -- Beatty, Linda -- Chan, Pak-Kei -- Juang, Yu-Chi -- Landry, Marie-Claude -- Yeh, Christina -- Zeqiraj, Elton -- Karamboulas, Konstantina -- Allali-Hassani, Abdellah -- Vedadi, Masoud -- Tyers, Mike -- Moffat, Jason -- Sicheri, Frank -- Pelletier, Laurence -- Durocher, Daniel -- Raught, Brian -- Rotin, Daniela -- Yang, Jianhua -- Moran, Michael F -- Dhe-Paganon, Sirano -- Sidhu, Sachdev S -- 092076/Wellcome Trust/United Kingdom -- 092381/Wellcome Trust/United Kingdom -- 1R01NS072420-01/Canadian Institutes of Health Research/Canada -- MOP-102536/Canadian Institutes of Health Research/Canada -- MOP-111149/Canadian Institutes of Health Research/Canada -- MOP-13494/Canadian Institutes of Health Research/Canada -- MOP-57795/Canadian Institutes of Health Research/Canada -- R01 NS072420/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2013 Feb 1;339(6119):590-5. doi: 10.1126/science.1230161. Epub 2013 Jan 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23287719" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; *Combinatorial Chemistry Techniques ; Conserved Sequence ; Drug Design ; Endopeptidases/chemistry/*metabolism ; HEK293 Cells ; Humans ; Molecular Sequence Data ; Protease Inhibitors/chemistry/*isolation & purification/pharmacology ; Protein Conformation ; Protein Structure, Secondary ; Small Molecule Libraries ; Ubiquitin/chemistry/genetics/*metabolism ; Ubiquitin Thiolesterase/chemistry/*metabolism ; Ubiquitin-Conjugating Enzymes/chemistry/metabolism ; Ubiquitin-Protein Ligases/chemistry/metabolism ; Ubiquitination/*drug effects
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  • 85
    Publication Date: 2013-03-29
    Description: Protein N-myristoylation is a 14-carbon fatty-acid modification that is conserved across eukaryotic species and occurs on nearly 1% of the cellular proteome. The ability of the myristoyl group to facilitate dynamic protein-protein and protein-membrane interactions (known as the myristoyl switch) makes it an essential feature of many signal transduction systems. Thus pathogenic strategies that facilitate protein demyristoylation would markedly alter the signalling landscape of infected host cells. Here we describe an irreversible mechanism of protein demyristoylation catalysed by invasion plasmid antigen J (IpaJ), a previously uncharacterized Shigella flexneri type III effector protein with cysteine protease activity. A yeast genetic screen for IpaJ substrates identified ADP-ribosylation factor (ARF)1p and ARF2p, small molecular mass GTPases that regulate cargo transport through the Golgi apparatus. Mass spectrometry showed that IpaJ cleaved the peptide bond between N-myristoylated glycine-2 and asparagine-3 of human ARF1, thereby providing a new mechanism for host secretory inhibition by a bacterial pathogen. We further demonstrate that IpaJ cleaves an array of N-myristoylated proteins involved in cellular growth, signal transduction, autophagasome maturation and organelle function. Taken together, these findings show a previously unrecognized pathogenic mechanism for the site-specific elimination of N-myristoyl protein modification.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3722872/" 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/PMC3722872/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Burnaevskiy, Nikolay -- Fox, Thomas G -- Plymire, Daniel A -- Ertelt, James M -- Weigele, Bethany A -- Selyunin, Andrey S -- Way, Sing Sing -- Patrie, Steven M -- Alto, Neal M -- 5T32AI007520/AI/NIAID NIH HHS/ -- R01 AI083359/AI/NIAID NIH HHS/ -- R01 AI087830/AI/NIAID NIH HHS/ -- R01 AI100934/AI/NIAID NIH HHS/ -- R01 GM100486/GM/NIGMS NIH HHS/ -- R01AI083359/AI/NIAID NIH HHS/ -- R01GM100486/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Apr 4;496(7443):106-9. doi: 10.1038/nature12004. Epub 2013 Mar 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8816, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23535599" target="_blank"〉PubMed〈/a〉
    Keywords: ADP-Ribosylation Factor 1/chemistry/metabolism ; ADP-Ribosylation Factors/metabolism ; Amino Acid Sequence ; Animals ; Antigens, Bacterial/*metabolism ; Asparagine/metabolism ; Autophagy ; Biocatalysis ; Cysteine Proteases/metabolism ; Dysentery, Bacillary ; Female ; Glycine/metabolism ; Golgi Apparatus/metabolism/pathology ; HEK293 Cells ; HeLa Cells ; Humans ; Listeria monocytogenes/physiology ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Myristic Acid/*metabolism ; Phagosomes/metabolism ; *Protein Processing, Post-Translational ; *Proteolysis ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/metabolism ; Sequence Alignment ; Shigella flexneri/enzymology/*metabolism ; Signal Transduction ; Substrate Specificity ; Virulence ; Virulence Factors/*metabolism
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  • 86
    Publication Date: 2013-03-29
    Description: Multidrug and toxic compound extrusion (MATE) family transporters are conserved in the three primary domains of life (Archaea, Bacteria and Eukarya), and export xenobiotics using an electrochemical gradient of H(+) or Na(+) across the membrane. MATE transporters confer multidrug resistance to bacterial pathogens and cancer cells, thus causing critical reductions in the therapeutic efficacies of antibiotics and anti-cancer drugs, respectively. Therefore, the development of MATE inhibitors has long been awaited in the field of clinical medicine. Here we present the crystal structures of the H(+)-driven MATE transporter from Pyrococcus furiosus in two distinct apo-form conformations, and in complexes with a derivative of the antibacterial drug norfloxacin and three in vitro selected thioether-macrocyclic peptides, at 2.1-3.0 A resolutions. The structures, combined with functional analyses, show that the protonation of Asp 41 on the amino (N)-terminal lobe induces the bending of TM1, which in turn collapses the N-lobe cavity, thereby extruding the substrate drug to the extracellular space. Moreover, the macrocyclic peptides bind the central cleft in distinct manners, which correlate with their inhibitory activities. The strongest inhibitory peptide that occupies the N-lobe cavity may pave the way towards the development of efficient inhibitors against MATE transporters.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tanaka, Yoshiki -- Hipolito, Christopher J -- Maturana, Andres D -- Ito, Koichi -- Kuroda, Teruo -- Higuchi, Takashi -- Katoh, Takayuki -- Kato, Hideaki E -- Hattori, Motoyuki -- Kumazaki, Kaoru -- Tsukazaki, Tomoya -- Ishitani, Ryuichiro -- Suga, Hiroaki -- Nureki, Osamu -- England -- Nature. 2013 Apr 11;496(7444):247-51. doi: 10.1038/nature12014. Epub 2013 Mar 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23535598" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Antiporters/*chemistry/*metabolism ; Apoproteins/chemistry/metabolism ; Archaeal Proteins/*chemistry/*metabolism ; Aspartic Acid/chemistry ; Crystallography, X-Ray ; DNA Mutational Analysis ; Macrocyclic Compounds/chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Norfloxacin/chemistry/metabolism ; Peptides/chemistry/metabolism ; Protein Conformation ; Protons ; Pyrococcus furiosus/*chemistry ; Structure-Activity Relationship ; Sulfides/chemistry/metabolism
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  • 87
    Publication Date: 2013-07-19
    Description: Structural analysis of class B G-protein-coupled receptors (GPCRs), cell-surface proteins that respond to peptide hormones, has been restricted to the amino-terminal extracellular domain, thus providing little understanding of the membrane-spanning signal transduction domain. The corticotropin-releasing factor receptor type 1 is a class B receptor which mediates the response to stress and has been considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of the human corticotropin-releasing factor receptor type 1 in complex with the small-molecule antagonist CP-376395. The structure provides detailed insight into the architecture of class B receptors. Atomic details of the interactions of the receptor with the non-peptide ligand that binds deep within the receptor are described. This structure provides a model for all class B GPCRs and may aid in the design of new small-molecule drugs for diseases of brain and metabolism.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hollenstein, Kaspar -- Kean, James -- Bortolato, Andrea -- Cheng, Robert K Y -- Dore, Andrew S -- Jazayeri, Ali -- Cooke, Robert M -- Weir, Malcolm -- Marshall, Fiona H -- England -- Nature. 2013 Jul 25;499(7459):438-43. doi: 10.1038/nature12357. Epub 2013 Jul 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City AL7 3AX, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23863939" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Aminopyridines/chemistry/metabolism/pharmacology ; Binding Sites ; Conserved Sequence ; Crystallography, X-Ray ; HEK293 Cells ; Humans ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Protein Binding ; Protein Structure, Tertiary ; Receptors, Corticotropin-Releasing Hormone/antagonists & ; inhibitors/*chemistry/*classification/metabolism ; Receptors, Dopamine D3/antagonists & inhibitors/chemistry/classification
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  • 88
    Publication Date: 2013-06-14
    Description: 53BP1 (also called TP53BP1) is a chromatin-associated factor that promotes immunoglobulin class switching and DNA double-strand-break (DSB) repair by non-homologous end joining. To accomplish its function in DNA repair, 53BP1 accumulates at DSB sites downstream of the RNF168 ubiquitin ligase. How ubiquitin recruits 53BP1 to break sites remains unknown as its relocalization involves recognition of histone H4 Lys 20 (H4K20) methylation by its Tudor domain. Here we elucidate how vertebrate 53BP1 is recruited to the chromatin that flanks DSB sites. We show that 53BP1 recognizes mononucleosomes containing dimethylated H4K20 (H4K20me2) and H2A ubiquitinated on Lys 15 (H2AK15ub), the latter being a product of RNF168 action on chromatin. 53BP1 binds to nucleosomes minimally as a dimer using its previously characterized methyl-lysine-binding Tudor domain and a carboxy-terminal extension, termed the ubiquitination-dependent recruitment (UDR) motif, which interacts with the epitope formed by H2AK15ub and its surrounding residues on the H2A tail. 53BP1 is therefore a bivalent histone modification reader that recognizes a histone 'code' produced by DSB signalling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955401/" 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/PMC3955401/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fradet-Turcotte, Amelie -- Canny, Marella D -- Escribano-Diaz, Cristina -- Orthwein, Alexandre -- Leung, Charles C Y -- Huang, Hao -- Landry, Marie-Claude -- Kitevski-LeBlanc, Julianne -- Noordermeer, Sylvie M -- Sicheri, Frank -- Durocher, Daniel -- 84297-1/Canadian Institutes of Health Research/Canada -- 84297-2/Canadian Institutes of Health Research/Canada -- MOP84297/Canadian Institutes of Health Research/Canada -- England -- Nature. 2013 Jul 4;499(7456):50-4. doi: 10.1038/nature12318. Epub 2013 Jun 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23760478" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Cell Cycle Proteins/chemistry/metabolism ; Cell Line ; Chromosomal Proteins, Non-Histone/chemistry/deficiency/genetics ; DNA Breaks, Double-Stranded ; *DNA Damage ; DNA-Binding Proteins/chemistry/deficiency/genetics ; Female ; Histones/*chemistry/*metabolism ; Humans ; Intracellular Signaling Peptides and ; Proteins/chemistry/deficiency/genetics/*metabolism ; Lysine/*metabolism ; Male ; Mice ; Molecular Sequence Data ; Mutant Proteins/chemistry/metabolism ; Nuclear Proteins/chemistry/metabolism ; Nucleosomes/chemistry/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Schizosaccharomyces ; Schizosaccharomyces pombe Proteins/chemistry/metabolism ; Signal Transduction ; Ubiquitin/*metabolism ; *Ubiquitination
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  • 89
    Publication Date: 2013-03-12
    Description: The regulated loading of the Mcm2-7 DNA helicase (comprising six related subunits, Mcm2 to Mcm7) into pre-replicative complexes at multiple replication origins ensures precise once per cell cycle replication in eukaryotic cells. The origin recognition complex (ORC), Cdc6 and Cdt1 load Mcm2-7 into a double hexamer bound around duplex DNA in an ATP-dependent reaction, but the molecular mechanism of this origin 'licensing' is still poorly understood. Here we show that both Mcm2-7 hexamers in Saccharomyces cerevisiae are recruited to origins by an essential, conserved carboxy-terminal domain of Mcm3 that interacts with and stimulates the ATPase activity of ORC-Cdc6. ATP hydrolysis can promote Mcm2-7 loading, but can also promote Mcm2-7 release if components are missing or if ORC has been inactivated by cyclin-dependent kinase phosphorylation. Our work provides new insights into how origins are licensed and reveals a novel ATPase-dependent mechanism contributing to precise once per cell cycle replication.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Frigola, Jordi -- Remus, Dirk -- Mehanna, Amina -- Diffley, John F X -- Cancer Research UK/United Kingdom -- England -- Nature. 2013 Mar 21;495(7441):339-43. doi: 10.1038/nature11920. Epub 2013 Mar 10.〈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/23474987" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/*metabolism ; Adenosine Triphosphate/metabolism ; Amino Acid Sequence ; Cell Cycle Proteins/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; DNA Replication/*genetics ; DNA-Binding Proteins/metabolism ; Enzyme Activation ; Hydrolysis ; Minichromosome Maintenance Complex Component 3 ; Minichromosome Maintenance Complex Component 7 ; Nuclear Proteins/metabolism ; Protein Binding ; Replication Origin/*genetics ; Saccharomyces cerevisiae/cytology/enzymology/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Sequence Alignment
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  • 90
    Publication Date: 2013-12-18
    Description: Strigolactones (SLs), a newly discovered class of carotenoid-derived phytohormones, are essential for developmental processes that shape plant architecture and interactions with parasitic weeds and symbiotic arbuscular mycorrhizal fungi. Despite the rapid progress in elucidating the SL biosynthetic pathway, the perception and signalling mechanisms of SL remain poorly understood. Here we show that DWARF 53 (D53) acts as a repressor of SL signalling and that SLs induce its degradation. We find that the rice (Oryza sativa) d53 mutant, which produces an exaggerated number of tillers compared to wild-type plants, is caused by a gain-of-function mutation and is insensitive to exogenous SL treatment. The D53 gene product shares predicted features with the class I Clp ATPase proteins and can form a complex with the alpha/beta hydrolase protein DWARF 14 (D14) and the F-box protein DWARF 3 (D3), two previously identified signalling components potentially responsible for SL perception. We demonstrate that, in a D14- and D3-dependent manner, SLs induce D53 degradation by the proteasome and abrogate its activity in promoting axillary bud outgrowth. Our combined genetic and biochemical data reveal that D53 acts as a repressor of the SL signalling pathway, whose hormone-induced degradation represents a key molecular link between SL perception and responses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096652/" 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/PMC4096652/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Feng -- Lin, Qibing -- Zhu, Lihong -- Ren, Yulong -- Zhou, Kunneng -- Shabek, Nitzan -- Wu, Fuqing -- Mao, Haibin -- Dong, Wei -- Gan, Lu -- Ma, Weiwei -- Gao, He -- Chen, Jun -- Yang, Chao -- Wang, Dan -- Tan, Junjie -- Zhang, Xin -- Guo, Xiuping -- Wang, Jiulin -- Jiang, Ling -- Liu, Xi -- Chen, Weiqi -- Chu, Jinfang -- Yan, Cunyu -- Ueno, Kotomi -- Ito, Shinsaku -- Asami, Tadao -- Cheng, Zhijun -- Wang, Jie -- Lei, Cailin -- Zhai, Huqu -- Wu, Chuanyin -- Wang, Haiyang -- Zheng, Ning -- Wan, Jianmin -- R01 CA107134/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Dec 19;504(7480):406-10. doi: 10.1038/nature12878. Epub 2013 Dec 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] National Key Laboratory for Crop Genetics and Germplasm Enhancement, Jiangsu Plant Gene Engineering Research Center, Nanjing Agricultural University, Nanjing 210095, China [2] National Key Facility for Crop Gene Resources and Genetic Improvement, Institute of Crop Science, Chinese Academy of Agricultural Sciences, Beijing 100081, China. ; National Key Facility for Crop Gene Resources and Genetic Improvement, Institute of Crop Science, Chinese Academy of Agricultural Sciences, Beijing 100081, China. ; National Key Laboratory for Crop Genetics and Germplasm Enhancement, Jiangsu Plant Gene Engineering Research Center, Nanjing Agricultural University, Nanjing 210095, China. ; 1] Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA [2] Howard Hughes Medical Institute, Box 357280, University of Washington, Seattle, Washington 98195, USA. ; National Centre for Plant Gene Research (Beijing), Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1-2 Beichen West Road, Beijing 100101, China. ; Department of Applied Biological Chemistry, The University of Tokyo, 1-1-1 Yayoi, Bunkyo, Tokyo 113-8657, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24336215" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cloning, Molecular ; Gene Expression Regulation, Plant ; Lactones/*metabolism ; Molecular Sequence Data ; Mutation/genetics ; Oryza/genetics/*metabolism ; Phenotype ; Plant Growth Regulators/*metabolism ; Plant Proteins/genetics/*metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; *Proteolysis ; SKP Cullin F-Box Protein Ligases/*metabolism ; *Signal Transduction
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  • 91
    Publication Date: 2013-05-03
    Description: The smoothened (SMO) receptor, a key signal transducer in the hedgehog signalling pathway, is responsible for the maintenance of normal embryonic development and is implicated in carcinogenesis. It is classified as a class frizzled (class F) G-protein-coupled receptor (GPCR), although the canonical hedgehog signalling pathway involves the GLI transcription factors and the sequence similarity with class A GPCRs is less than 10%. Here we report the crystal structure of the transmembrane domain of the human SMO receptor bound to the small-molecule antagonist LY2940680 at 2.5 A resolution. Although the SMO receptor shares the seven-transmembrane helical fold, most of the conserved motifs for class A GPCRs are absent, and the structure reveals an unusually complex arrangement of long extracellular loops stabilized by four disulphide bonds. The ligand binds at the extracellular end of the seven-transmembrane-helix bundle and forms extensive contacts with the loops.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657389/" 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/PMC3657389/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Chong -- Wu, Huixian -- Katritch, Vsevolod -- Han, Gye Won -- Huang, Xi-Ping -- Liu, Wei -- Siu, Fai Yiu -- Roth, Bryan L -- Cherezov, Vadim -- Stevens, Raymond C -- F32 DK088392/DK/NIDDK NIH HHS/ -- P50 GM073197/GM/NIGMS NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 DA027170/DA/NIDA NIH HHS/ -- R01 DA27170/DA/NIDA NIH HHS/ -- R01 MH061887/MH/NIMH NIH HHS/ -- R01MH61887/MH/NIMH NIH HHS/ -- U19 MH082441/MH/NIMH NIH HHS/ -- U19 MH82441/MH/NIMH NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 May 16;497(7449):338-43. doi: 10.1038/nature12167. Epub 2013 May 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23636324" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Antineoplastic Agents/*chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Disulfides/chemistry ; Frizzled Receptors/chemistry/classification ; Humans ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Phthalazines/*chemistry/metabolism ; Protein Structure, Tertiary ; Receptors, G-Protein-Coupled/*chemistry/classification/metabolism ; Structural Homology, Protein
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  • 92
    Publication Date: 2013-07-26
    Description: A key event in the domestication and breeding of the oil palm Elaeis guineensis was loss of the thick coconut-like shell surrounding the kernel. Modern E. guineensis has three fruit forms, dura (thick-shelled), pisifera (shell-less) and tenera (thin-shelled), a hybrid between dura and pisifera. The pisifera palm is usually female-sterile. The tenera palm yields far more oil than dura, and is the basis for commercial palm oil production in all of southeast Asia. Here we describe the mapping and identification of the SHELL gene responsible for the different fruit forms. Using homozygosity mapping by sequencing, we found two independent mutations in the DNA-binding domain of a homologue of the MADS-box gene SEEDSTICK (STK, also known as AGAMOUS-LIKE 11), which controls ovule identity and seed development in Arabidopsis. The SHELL gene is responsible for the tenera phenotype in both cultivated and wild palms from sub-Saharan Africa, and our findings provide a genetic explanation for the single gene hybrid vigour (or heterosis) attributed to SHELL, via heterodimerization. This gene mutation explains the single most important economic trait in oil palm, and has implications for the competing interests of global edible oil production, biofuels and rainforest conservation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209285/" 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/PMC4209285/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Singh, Rajinder -- Low, Eng-Ti Leslie -- Ooi, Leslie Cheng-Li -- Ong-Abdullah, Meilina -- Ting, Ngoot-Chin -- Nagappan, Jayanthi -- Nookiah, Rajanaidu -- Amiruddin, Mohd Din -- Rosli, Rozana -- Manaf, Mohamad Arif Abdul -- Chan, Kuang-Lim -- Halim, Mohd Amin -- Azizi, Norazah -- Lakey, Nathan -- Smith, Steven W -- Budiman, Muhammad A -- Hogan, Michael -- Bacher, Blaire -- Van Brunt, Andrew -- Wang, Chunyan -- Ordway, Jared M -- Sambanthamurthi, Ravigadevi -- Martienssen, Robert A -- R01 GM067014/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Aug 15;500(7462):340-4. doi: 10.1038/nature12356. Epub 2013 Jul 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Malaysian Palm Oil Board, 6, Persiaran Institusi, Bandar Baru Bangi, 43000 Kajang, Selangor, Malaysia. raviga@mpob.gov.my〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23883930" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arabidopsis Proteins/genetics ; Arecaceae/*genetics/*metabolism ; Chromosome Mapping ; Gene Expression Profiling ; Gene Expression Regulation, Plant ; Genes, Plant/*genetics ; Genetic Variation ; Homozygote ; MADS Domain Proteins/genetics ; Molecular Sequence Data ; Mutation ; *Plant Oils ; Sequence Alignment
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  • 93
    Publication Date: 2013-10-29
    Description: Integrins have a critical role in thrombosis and haemostasis. Antagonists of the platelet integrin alphaIIbbeta3 are potent anti-thrombotic drugs, but also have the life-threatening adverse effect of causing bleeding. It is therefore desirable to develop new antagonists that do not cause bleeding. Integrins transmit signals bidirectionally. Inside-out signalling activates integrins through a talin-dependent mechanism. Integrin ligation mediates thrombus formation and outside-in signalling, which requires Galpha13 and greatly expands thrombi. Here we show that Galpha13 and talin bind to mutually exclusive but distinct sites within the integrin beta3 cytoplasmic domain in opposing waves. The first talin-binding wave mediates inside-out signalling and also ligand-induced integrin activation, but is not required for outside-in signalling. Integrin ligation induces transient talin dissociation and Galpha13 binding to an EXE motif (in which X denotes any residue), which selectively mediates outside-in signalling and platelet spreading. The second talin-binding wave is associated with clot retraction. An EXE-motif-based inhibitor of Galpha13-integrin interaction selectively abolishes outside-in signalling without affecting integrin ligation, and suppresses occlusive arterial thrombosis without affecting bleeding time. Thus, we have discovered a new mechanism for the directional switch of integrin signalling and, on the basis of this mechanism, designed a potent new anti-thrombotic drug that does not cause bleeding.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3823815/" 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/PMC3823815/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shen, Bo -- Zhao, Xiaojuan -- O'Brien, Kelly A -- Stojanovic-Terpo, Aleksandra -- Delaney, M Keegan -- Kim, Kyungho -- Cho, Jaehyung -- Lam, Stephen C-T -- Du, Xiaoping -- HL062350/HL/NHLBI NIH HHS/ -- HL080264/HL/NHLBI NIH HHS/ -- HL109439/HL/NHLBI NIH HHS/ -- R01 HL080264/HL/NHLBI NIH HHS/ -- R01 HL109439/HL/NHLBI NIH HHS/ -- T32 HL007829/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 Nov 7;503(7474):131-5. doi: 10.1038/nature12613. Epub 2013 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, Illinois 60612, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24162846" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Antithrombins/adverse effects/*pharmacology/therapeutic use ; Binding Sites ; Bleeding Time ; *Cell Polarity ; Cytoplasm/metabolism ; GTP-Binding Protein alpha Subunits, G12-G13/metabolism ; Hemorrhage/chemically induced ; Humans ; Integrin beta3/chemistry/genetics/metabolism ; Integrins/chemistry/deficiency/genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Platelet Glycoprotein GPIIb-IIIa Complex/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Signal Transduction/*drug effects ; Talin/metabolism ; Thrombosis/*drug therapy/metabolism/pathology
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  • 94
    Publication Date: 2013-07-19
    Description: Binding of the glucagon peptide to the glucagon receptor (GCGR) triggers the release of glucose from the liver during fasting; thus GCGR plays an important role in glucose homeostasis. Here we report the crystal structure of the seven transmembrane helical domain of human GCGR at 3.4 A resolution, complemented by extensive site-specific mutagenesis, and a hybrid model of glucagon bound to GCGR to understand the molecular recognition of the receptor for its native ligand. Beyond the shared seven transmembrane fold, the GCGR transmembrane domain deviates from class A G-protein-coupled receptors with a large ligand-binding pocket and the first transmembrane helix having a 'stalk' region that extends three alpha-helical turns above the plane of the membrane. The stalk positions the extracellular domain (~12 kilodaltons) relative to the membrane to form the glucagon-binding site that captures the peptide and facilitates the insertion of glucagon's amino terminus into the seven transmembrane domain.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820480/" 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/PMC3820480/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Siu, Fai Yiu -- He, Min -- de Graaf, Chris -- Han, Gye Won -- Yang, Dehua -- Zhang, Zhiyun -- Zhou, Caihong -- Xu, Qingping -- Wacker, Daniel -- Joseph, Jeremiah S -- Liu, Wei -- Lau, Jesper -- Cherezov, Vadim -- Katritch, Vsevolod -- Wang, Ming-Wei -- Stevens, Raymond C -- F32 DK088392/DK/NIDDK NIH HHS/ -- P50 GM073197/GM/NIGMS NIH HHS/ -- P50GM073197/GM/NIGMS NIH HHS/ -- U54 GM094586/GM/NIGMS NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Jul 25;499(7459):444-9. doi: 10.1038/nature12393. Epub 2013 Jul 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23863937" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding Sites ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Glucagon/chemistry/metabolism ; Humans ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Protein Binding ; Protein Structure, Tertiary ; Receptors, CXCR4/chemistry/classification ; Receptors, Glucagon/*chemistry/*classification/genetics/metabolism
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  • 95
    Publication Date: 2013-08-02
    Description: Prion infections cause lethal neurodegeneration. This process requires the cellular prion protein (PrP(C); ref. 1), which contains a globular domain hinged to a long amino-proximal flexible tail. Here we describe rapid neurotoxicity in mice and cerebellar organotypic cultured slices exposed to ligands targeting the alpha1 and alpha3 helices of the PrP(C) globular domain. Ligands included seven distinct monoclonal antibodies, monovalent Fab1 fragments and recombinant single-chain variable fragment miniantibodies. Similar to prion infections, the toxicity of globular domain ligands required neuronal PrP(C), was exacerbated by PrP(C) overexpression, was associated with calpain activation and was antagonized by calpain inhibitors. Neurodegeneration was accompanied by a burst of reactive oxygen species, and was suppressed by antioxidants. Furthermore, genetic ablation of the superoxide-producing enzyme NOX2 (also known as CYBB) protected mice from globular domain ligand toxicity. We also found that neurotoxicity was prevented by deletions of the octapeptide repeats within the flexible tail. These deletions did not appreciably compromise globular domain antibody binding, suggesting that the flexible tail is required to transmit toxic signals that originate from the globular domain and trigger oxidative stress and calpain activation. Supporting this view, various octapeptide ligands were not only innocuous to both cerebellar organotypic cultured slices and mice, but also prevented the toxicity of globular domain ligands while not interfering with their binding. We conclude that PrP(C) consists of two functionally distinct modules, with the globular domain and the flexible tail exerting regulatory and executive functions, respectively. Octapeptide ligands also prolonged the life of mice expressing the toxic PrP(C) mutant, PrP(Delta94-134), indicating that the flexible tail mediates toxicity in two distinct PrP(C)-related conditions. Flexible tail-mediated toxicity may conceivably play a role in further prion pathologies, such as familial Creutzfeldt-Jakob disease in humans bearing supernumerary octapeptides.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sonati, Tiziana -- Reimann, Regina R -- Falsig, Jeppe -- Baral, Pravas Kumar -- O'Connor, Tracy -- Hornemann, Simone -- Yaganoglu, Sine -- Li, Bei -- Herrmann, Uli S -- Wieland, Barbara -- Swayampakula, Mridula -- Rahman, Muhammad Hafizur -- Das, Dipankar -- Kav, Nat -- Riek, Roland -- Liberski, Pawel P -- James, Michael N G -- Aguzzi, Adriano -- England -- Nature. 2013 Sep 5;501(7465):102-6. doi: 10.1038/nature12402. Epub 2013 Jul 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Neuropathology, University Hospital Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23903654" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Antibodies/*immunology/*toxicity ; Antibodies, Monoclonal/immunology/toxicity ; Binding Sites, Antibody ; Calpain/metabolism ; Cerebellum ; Creutzfeldt-Jakob Syndrome/metabolism ; Cross-Linking Reagents ; Epitope Mapping ; Female ; Immunoglobulin Fab Fragments/immunology/toxicity ; In Vitro Techniques ; Ligands ; Male ; Membrane Glycoproteins/metabolism ; Mice ; Molecular Sequence Data ; NADPH Oxidase/metabolism ; Neurodegenerative Diseases/metabolism ; Oxidative Stress ; *Pliability ; PrPC Proteins/chemistry/genetics/immunology ; Prions/*chemistry/genetics/*immunology ; Reactive Oxygen Species/metabolism ; Sequence Deletion/genetics ; Single-Chain Antibodies/immunology/toxicity
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  • 96
    Publication Date: 2013-05-28
    Description: A complex interaction of signalling events, including the Wnt pathway, regulates sprouting of blood vessels from pre-existing vasculature during angiogenesis. Here we show that two distinct mutations in the (uro)chordate-specific gumby (also called Fam105b) gene cause an embryonic angiogenic phenotype in gumby mice. Gumby interacts with disheveled 2 (DVL2), is expressed in canonical Wnt-responsive endothelial cells and encodes an ovarian tumour domain class of deubiquitinase that specifically cleaves linear ubiquitin linkages. A crystal structure of gumby in complex with linear diubiquitin reveals how the identified mutations adversely affect substrate binding and catalytic function in line with the severity of their angiogenic phenotypes. Gumby interacts with HOIP (also called RNF31), a key component of the linear ubiquitin assembly complex, and decreases linear ubiquitination and activation of NF-kappaB-dependent transcription. This work provides support for the biological importance of linear (de)ubiquitination in angiogenesis, craniofacial and neural development and in modulating Wnt signalling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rivkin, Elena -- Almeida, Stephanie M -- Ceccarelli, Derek F -- Juang, Yu-Chi -- MacLean, Teresa A -- Srikumar, Tharan -- Huang, Hao -- Dunham, Wade H -- Fukumura, Ryutaro -- Xie, Gang -- Gondo, Yoichi -- Raught, Brian -- Gingras, Anne-Claude -- Sicheri, Frank -- Cordes, Sabine P -- IHO 94384/Canadian Institutes of Health Research/Canada -- MOP 111199/Canadian Institutes of Health Research/Canada -- MOP 97966/Canadian Institutes of Health Research/Canada -- MOP119289/Canadian Institutes of Health Research/Canada -- England -- Nature. 2013 Jun 20;498(7454):318-24. doi: 10.1038/nature12296. Epub 2013 May 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23708998" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/metabolism ; Alleles ; Amino Acid Sequence ; Animals ; Base Sequence ; Crystallography, X-Ray ; Embryo, Mammalian/blood supply/embryology/metabolism ; Endopeptidases/*chemistry/deficiency/genetics/*metabolism ; Female ; Gene Expression Profiling ; HEK293 Cells ; Humans ; Mice ; Models, Molecular ; Molecular Sequence Data ; *Neovascularization, Physiologic/genetics ; Phenotype ; Phosphoproteins/metabolism ; Protein Conformation ; Ubiquitin/*chemistry/*metabolism ; Ubiquitin-Protein Ligases/metabolism ; *Ubiquitination ; Wnt Signaling Pathway
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  • 97
    Publication Date: 2013-03-15
    Description: A hallmark of histone H3 lysine 9 (H3K9)-methylated heterochromatin, conserved from the fission yeast Schizosaccharomyces pombe to humans, is its ability to spread to adjacent genomic regions. Central to heterochromatin spread is heterochromatin protein 1 (HP1), which recognizes H3K9-methylated chromatin, oligomerizes and forms a versatile platform that participates in diverse nuclear functions, ranging from gene silencing to chromosome segregation. How HP1 proteins assemble on methylated nucleosomal templates and how the HP1-nucleosome complex achieves functional versatility remain poorly understood. Here we show that binding of the key S. pombe HP1 protein, Swi6, to methylated nucleosomes drives a switch from an auto-inhibited state to a spreading-competent state. In the auto-inhibited state, a histone-mimic sequence in one Swi6 monomer blocks methyl-mark recognition by the chromodomain of another monomer. Auto-inhibition is relieved by recognition of two template features, the H3K9 methyl mark and nucleosomal DNA. Cryo-electron-microscopy-based reconstruction of the Swi6-nucleosome complex provides the overall architecture of the spreading-competent state in which two unbound chromodomain sticky ends appear exposed. Disruption of the switch between the auto-inhibited and spreading-competent states disrupts heterochromatin assembly and gene silencing in vivo. These findings are reminiscent of other conditionally activated polymerization processes, such as actin nucleation, and open up a new class of regulatory mechanisms that operate on chromatin in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907283/" 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/PMC3907283/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Canzio, Daniele -- Liao, Maofu -- Naber, Nariman -- Pate, Edward -- Larson, Adam -- Wu, Shenping -- Marina, Diana B -- Garcia, Jennifer F -- Madhani, Hiten D -- Cooke, Roger -- Schuck, Peter -- Cheng, Yifan -- Narlikar, Geeta J -- AR053720/AR/NIAMS NIH HHS/ -- R01 AR062279/AR/NIAMS NIH HHS/ -- R01 GM071801/GM/NIGMS NIH HHS/ -- R01GM071801/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2013 Apr 18;496(7445):377-81. doi: 10.1038/nature12032. Epub 2013 Mar 13.〈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/23485968" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; *Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/*antagonists & ; inhibitors/*chemistry/*metabolism/ultrastructure ; Cryoelectron Microscopy ; Gene Silencing ; Heterochromatin/chemistry/*metabolism/ultrastructure ; Histones/chemistry/metabolism ; Methylation ; Models, Molecular ; Molecular Sequence Data ; Nucleosomes/chemistry/genetics/metabolism/ultrastructure ; Protein Structure, Tertiary ; Schizosaccharomyces/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/antagonists & ; inhibitors/*chemistry/*metabolism/ultrastructure ; Xenopus laevis
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 98
    Publication Date: 2013-04-05
    Description: Current human immunodeficiency virus-1 (HIV-1) vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in approximately 20% of HIV-1-infected individuals, and details of their generation could provide a blueprint for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection. The mature antibody, CH103, neutralized approximately 55% of HIV-1 isolates, and its co-crystal structure with the HIV-1 envelope protein gp120 revealed a new loop-based mechanism of CD4-binding-site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the unmutated common ancestor of the CH103 lineage avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data determine the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies, and provide insights into strategies to elicit similar antibodies by vaccination.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637846/" 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/PMC3637846/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liao, Hua-Xin -- Lynch, Rebecca -- Zhou, Tongqing -- Gao, Feng -- Alam, S Munir -- Boyd, Scott D -- Fire, Andrew Z -- Roskin, Krishna M -- Schramm, Chaim A -- Zhang, Zhenhai -- Zhu, Jiang -- Shapiro, Lawrence -- NISC Comparative Sequencing Program -- Mullikin, James C -- Gnanakaran, S -- Hraber, Peter -- Wiehe, Kevin -- Kelsoe, Garnett -- Yang, Guang -- Xia, Shi-Mao -- Montefiori, David C -- Parks, Robert -- Lloyd, Krissey E -- Scearce, Richard M -- Soderberg, Kelly A -- Cohen, Myron -- Kamanga, Gift -- Louder, Mark K -- Tran, Lillian M -- Chen, Yue -- Cai, Fangping -- Chen, Sheri -- Moquin, Stephanie -- Du, Xiulian -- Joyce, M Gordon -- Srivatsan, Sanjay -- Zhang, Baoshan -- Zheng, Anqi -- Shaw, George M -- Hahn, Beatrice H -- Kepler, Thomas B -- Korber, Bette T M -- Kwong, Peter D -- Mascola, John R -- Haynes, Barton F -- AI067854/AI/NIAID NIH HHS/ -- AI100645/AI/NIAID NIH HHS/ -- P30 AI050410/AI/NIAID NIH HHS/ -- UM1 AI100645/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2013 Apr 25;496(7446):469-76. doi: 10.1038/nature12053. Epub 2013 Apr 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Duke University Human Vaccine Institute, Departments of Medicine and Immunology, Duke University School of Medicine, Durham, North Carolina 27710, USA. hliao@duke.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23552890" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines/immunology ; Africa ; Amino Acid Sequence ; Antibodies, Monoclonal/chemistry/genetics/immunology ; Antibodies, Neutralizing/*chemistry/genetics/*immunology ; Antigens, CD4/chemistry/immunology ; Cell Lineage ; Cells, Cultured ; Clone Cells/cytology ; Cross Reactions/immunology ; Crystallography, X-Ray ; Epitopes/chemistry/immunology ; *Evolution, Molecular ; HIV Antibodies/*chemistry/genetics/*immunology ; HIV Envelope Protein gp120/chemistry/genetics/immunology/metabolism ; HIV-1/*chemistry/classification/*immunology ; Humans ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Neutralization Tests ; Phylogeny ; Protein Structure, Tertiary
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 99
    Publication Date: 2013-06-21
    Description: The naked mole rat (Heterocephalus glaber) displays exceptional longevity, with a maximum lifespan exceeding 30 years. This is the longest reported lifespan for a rodent species and is especially striking considering the small body mass of the naked mole rat. In comparison, a similarly sized house mouse has a maximum lifespan of 4 years. In addition to their longevity, naked mole rats show an unusual resistance to cancer. Multi-year observations of large naked mole-rat colonies did not detect a single incidence of cancer. Here we identify a mechanism responsible for the naked mole rat's cancer resistance. We found that naked mole-rat fibroblasts secrete extremely high-molecular-mass hyaluronan (HA), which is over five times larger than human or mouse HA. This high-molecular-mass HA accumulates abundantly in naked mole-rat tissues owing to the decreased activity of HA-degrading enzymes and a unique sequence of hyaluronan synthase 2 (HAS2). Furthermore, the naked mole-rat cells are more sensitive to HA signalling, as they have a higher affinity to HA compared with mouse or human cells. Perturbation of the signalling pathways sufficient for malignant transformation of mouse fibroblasts fails to transform naked mole-rat cells. However, once high-molecular-mass HA is removed by either knocking down HAS2 or overexpressing the HA-degrading enzyme, HYAL2, naked mole-rat cells become susceptible to malignant transformation and readily form tumours in mice. We speculate that naked mole rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels. This trait may have then been co-opted to provide cancer resistance and longevity to this species.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720720/" 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/PMC3720720/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tian, Xiao -- Azpurua, Jorge -- Hine, Christopher -- Vaidya, Amita -- Myakishev-Rempel, Max -- Ablaeva, Julia -- Mao, Zhiyong -- Nevo, Eviatar -- Gorbunova, Vera -- Seluanov, Andrei -- R01 AG027237/AG/NIA NIH HHS/ -- R01 AG031227/AG/NIA NIH HHS/ -- England -- Nature. 2013 Jul 18;499(7458):346-9. doi: 10.1038/nature12234. Epub 2013 Jun 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, University of Rochester, Rochester, New York 14627, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23783513" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Cell Proliferation ; Cell Transformation, Neoplastic/*metabolism ; Cells, Cultured ; Contact Inhibition ; Disease Resistance ; Fibroblasts/metabolism ; Glucuronosyltransferase/chemistry ; Guinea Pigs ; Humans ; Hyaluronic Acid/*metabolism ; Mice ; Mole Rats ; Molecular Sequence Data
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 100
    Publication Date: 2013-12-03
    Description: CAAX proteins have essential roles in multiple signalling pathways, controlling processes such as proliferation, differentiation and carcinogenesis. The approximately 120 mammalian CAAX proteins function at cellular membranes and include the Ras superfamily of small GTPases, nuclear lamins, the gamma-subunit of heterotrimeric GTPases, and several protein kinases and phosphatases. The proper localization of CAAX proteins to cell membranes is orchestrated by a series of post-translational modifications of the carboxy-terminal CAAX motifs (where C is cysteine, A is an aliphatic amino acid and X is any amino acid). These reactions involve prenylation of the cysteine residue, cleavage at the AAX tripeptide and methylation of the carboxyl-prenylated cysteine residue. The major CAAX protease activity is mediated by Rce1 (Ras and a-factor converting enzyme 1), an intramembrane protease (IMP) of the endoplasmic reticulum. Information on the architecture and proteolytic mechanism of Rce1 has been lacking. Here we report the crystal structure of a Methanococcus maripaludis homologue of Rce1, whose endopeptidase specificity for farnesylated peptides mimics that of eukaryotic Rce1. Its structure, comprising eight transmembrane alpha-helices, and catalytic site are distinct from those of other IMPs. The catalytic residues are located approximately 10 A into the membrane and are exposed to the cytoplasm and membrane through a conical cavity that accommodates the prenylated CAAX substrate. We propose that the farnesyl lipid binds to a site at the opening of two transmembrane alpha-helices, which results in the scissile bond being positioned adjacent to a glutamate-activated nucleophilic water molecule. This study suggests that Rce1 is the founding member of a novel IMP family, the glutamate IMPs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864837/" 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/PMC3864837/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Manolaridis, Ioannis -- Kulkarni, Kiran -- Dodd, Roger B -- Ogasawara, Satoshi -- Zhang, Ziguo -- Bineva, Ganka -- O'Reilly, Nicola -- Hanrahan, Sarah J -- Thompson, Andrew J -- Cronin, Nora -- Iwata, So -- Barford, David -- 100140/Wellcome Trust/United Kingdom -- A2560/Cancer Research UK/United Kingdom -- A7403/Cancer Research UK/United Kingdom -- A8022/Cancer Research UK/United Kingdom -- BB/G023425/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2013 Dec 12;504(7479):301-5. doi: 10.1038/nature12754. Epub 2013 Dec 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2]. ; 1] Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2] [3] Division of Biological Sciences, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India (K.K.); Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK (R.B.D.). ; 1] Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2] Division of Biological Sciences, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India (K.K.); Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK (R.B.D.). ; 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. ; Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. ; Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. ; 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 [3] Department of Life Sciences, Imperial College, London SW7 2AZ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24291792" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Archaeal Proteins/chemistry/metabolism ; *Biocatalysis ; Conserved Sequence ; Crystallography, X-Ray ; Cysteine/metabolism ; DNA-Binding Proteins/chemistry/metabolism ; Endopeptidases/chemistry/metabolism ; Endoplasmic Reticulum/enzymology ; Escherichia coli Proteins/chemistry/metabolism ; Glutamic Acid/metabolism ; Humans ; Membrane Proteins/*chemistry/metabolism ; Metalloendopeptidases/chemistry/metabolism ; Methanococcus/*enzymology ; Mice ; Models, Molecular ; Molecular Sequence Data ; Peptide Hydrolases/*chemistry/classification/*metabolism ; *Prenylation ; Protein Structure, Tertiary ; Proto-Oncogene Proteins p21(ras)/chemistry/*metabolism ; Signal Transduction ; Substrate Specificity
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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