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  • Protein Binding  (66)
  • Nature Publishing Group (NPG)  (66)
  • Blackwell Publishing Ltd
  • Public Library of Science
  • 2015-2019  (66)
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  • 1
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    Crystal structures of a polypeptide processing and secretion transporter (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-07-24
    Description: Bacteria secrete peptides and proteins to communicate, to poison competitors, and to manipulate host cells. Among the various protein-translocation machineries, the peptidase-containing ATP-binding cassette transporters (PCATs) are appealingly simple. Each PCAT contains two peptidase domains that cleave the secretion signal from the substrate, two transmembrane domains that form a translocation pathway, and two nucleotide-binding domains that hydrolyse ATP. In Gram-positive bacteria, PCATs function both as maturation proteases and exporters for quorum-sensing or antimicrobial polypeptides. In Gram-negative bacteria, PCATs interact with two other membrane proteins to form the type 1 secretion system. Here we present crystal structures of PCAT1 from Clostridium thermocellum in two different conformations. These structures, accompanied by biochemical data, show that the translocation pathway is a large alpha-helical barrel sufficient to accommodate small folded proteins. ATP binding alternates access to the transmembrane pathway and also regulates the protease activity, thereby coupling substrate processing to translocation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lin, David Yin-wei -- Huang, Shuo -- Chen, Jue -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jul 23;523(7561):425-30. doi: 10.1038/nature14623.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Laboratory of Membrane Biology and Biophysics, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA [2] Howard Hughes Medical Institute, 1230 York Avenue, New York, New York 10065, USA. ; Howard Hughes Medical Institute, 1230 York Avenue, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26201595" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/*chemistry/metabolism ; Adenosine Triphosphate/deficiency/metabolism ; Clostridium thermocellum/*chemistry ; Crystallography, X-Ray ; Models, Molecular ; Peptides/*metabolism/secretion ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Structure-Activity Relationship
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    Transcription factor binding dynamics during human ES cell differentiation (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-02-20
    Description: Pluripotent stem cells provide a powerful system to dissect the underlying molecular dynamics that regulate cell fate changes during mammalian development. Here we report the integrative analysis of genome-wide binding data for 38 transcription factors with extensive epigenome and transcriptional data across the differentiation of human embryonic stem cells to the three germ layers. We describe core regulatory dynamics and show the lineage-specific behaviour of selected factors. In addition to the orchestrated remodelling of the chromatin landscape, we find that the binding of several transcription factors is strongly associated with specific loss of DNA methylation in one germ layer, and in many cases a reciprocal gain in the other layers. Taken together, our work shows context-dependent rewiring of transcription factor binding, downstream signalling effectors, and the epigenome during human embryonic stem cell differentiation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499331/" 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/PMC4499331/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tsankov, Alexander M -- Gu, Hongcang -- Akopian, Veronika -- Ziller, Michael J -- Donaghey, Julie -- Amit, Ido -- Gnirke, Andreas -- Meissner, Alexander -- 5F32DK095537/DK/NIDDK NIH HHS/ -- P01 GM099117/GM/NIGMS NIH HHS/ -- P01GM099117/GM/NIGMS NIH HHS/ -- P50HG006193/HG/NHGRI NIH HHS/ -- U01 ES017155/ES/NIEHS NIH HHS/ -- U01ES017155/ES/NIEHS NIH HHS/ -- England -- Nature. 2015 Feb 19;518(7539):344-9. doi: 10.1038/nature14233.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; 1] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Immunology, Weizmann Institute, Rehovot, 76100 Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25693565" target="_blank"〉PubMed〈/a〉
    Keywords: *Cell Differentiation/genetics ; Cell Lineage ; Chromatin/chemistry/genetics/metabolism ; Chromatin Assembly and Disassembly/genetics ; DNA Methylation ; Embryonic Stem Cells/*cytology/*metabolism ; Enhancer Elements, Genetic/genetics ; Epigenesis, Genetic/genetics ; Epigenomics ; Genome, Human/genetics ; Germ Layers/cytology/metabolism ; Histones/chemistry/metabolism ; Humans ; Protein Binding ; Signal Transduction ; Transcription Factors/*metabolism ; Transcription, Genetic/genetics
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  • 3
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    Multiple mechanisms for CRISPR-Cas inhibition by anti-CRISPR proteins (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-09-30
    Description: The battle for survival between bacteria and the viruses that infect them (phages) has led to the evolution of many bacterial defence systems and phage-encoded antagonists of these systems. Clustered regularly interspaced short palindromic repeats (CRISPR) and the CRISPR-associated (cas) genes comprise an adaptive immune system that is one of the most widespread means by which bacteria defend themselves against phages. We identified the first examples of proteins produced by phages that inhibit a CRISPR-Cas system. Here we performed biochemical and in vivo investigations of three of these anti-CRISPR proteins, and show that each inhibits CRISPR-Cas activity through a distinct mechanism. Two block the DNA-binding activity of the CRISPR-Cas complex, yet do this by interacting with different protein subunits, and using steric or non-steric modes of inhibition. The third anti-CRISPR protein operates by binding to the Cas3 helicase-nuclease and preventing its recruitment to the DNA-bound CRISPR-Cas complex. In vivo, this anti-CRISPR can convert the CRISPR-Cas system into a transcriptional repressor, providing the first example-to our knowledge-of modulation of CRISPR-Cas activity by a protein interactor. The diverse sequences and mechanisms of action of these anti-CRISPR proteins imply an independent evolution, and foreshadow the existence of other means by which proteins may alter CRISPR-Cas function.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bondy-Denomy, Joseph -- Garcia, Bianca -- Strum, Scott -- Du, Mingjian -- Rollins, MaryClare F -- Hidalgo-Reyes, Yurima -- Wiedenheft, Blake -- Maxwell, Karen L -- Davidson, Alan R -- MOP-130482/Canadian Institutes of Health Research/Canada -- MOP-136845/Canadian Institutes of Health Research/Canada -- P20GM103500/GM/NIGMS NIH HHS/ -- R01GM108888/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Oct 1;526(7571):136-9. doi: 10.1038/nature15254. Epub 2015 Sep 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Department of Microbiology and Immunology, Montana State University, Bozeman, Montana 59717, USA. ; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26416740" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteria/*metabolism/*virology ; Bacteriophages/*metabolism ; CRISPR-Associated Proteins/*antagonists & inhibitors/metabolism ; CRISPR-Cas Systems/genetics/*physiology ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; DNA Helicases/antagonists & inhibitors/metabolism ; DNA, Viral/metabolism ; DNA-Binding Proteins/antagonists & inhibitors/metabolism ; Endonucleases/antagonists & inhibitors/metabolism ; *Evolution, Molecular ; Protein Binding ; Protein Subunits/antagonists & inhibitors/metabolism ; Repressor Proteins/genetics/metabolism ; Substrate Specificity ; Viral Proteins/*metabolism
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  • 4
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    Regulation of endoplasmic reticulum turnover by selective autophagy (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-06-05
    Description: The endoplasmic reticulum (ER) is the largest intracellular endomembrane system, enabling protein and lipid synthesis, ion homeostasis, quality control of newly synthesized proteins and organelle communication. Constant ER turnover and modulation is needed to meet different cellular requirements and autophagy has an important role in this process. However, its underlying regulatory mechanisms remain unexplained. Here we show that members of the FAM134 reticulon protein family are ER-resident receptors that bind to autophagy modifiers LC3 and GABARAP, and facilitate ER degradation by autophagy ('ER-phagy'). Downregulation of FAM134B protein in human cells causes an expansion of the ER, while FAM134B overexpression results in ER fragmentation and lysosomal degradation. Mutant FAM134B proteins that cause sensory neuropathy in humans are unable to act as ER-phagy receptors. Consistently, disruption of Fam134b in mice causes expansion of the ER, inhibits ER turnover, sensitizes cells to stress-induced apoptotic cell death and leads to degeneration of sensory neurons. Therefore, selective ER-phagy via FAM134 proteins is indispensable for mammalian cell homeostasis and controls ER morphology and turnover in mice and humans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Khaminets, Aliaksandr -- Heinrich, Theresa -- Mari, Muriel -- Grumati, Paolo -- Huebner, Antje K -- Akutsu, Masato -- Liebmann, Lutz -- Stolz, Alexandra -- Nietzsche, Sandor -- Koch, Nicole -- Mauthe, Mario -- Katona, Istvan -- Qualmann, Britta -- Weis, Joachim -- Reggiori, Fulvio -- Kurth, Ingo -- Hubner, Christian A -- Dikic, Ivan -- England -- Nature. 2015 Jun 18;522(7556):354-8. doi: 10.1038/nature14498. Epub 2015 Jun 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. ; Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Kollegiengasse 10, 07743 Jena, Germany. ; 1] Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands [2] Department of Cell Biology, University Medical Center Utrecht, University of Groningen, Antonious Deusinglaan 1, 3713 AV Groningen, The Netherlands. ; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Riedberg Campus, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany. ; Electron Microscopy Center, Jena University Hospital, Friedrich-Schiller-University Jena, Ziegelmuhlenweg 1, 07743 Jena, Germany. ; Institute for Biochemistry I, Jena University Hospital, Friedrich-Schiller-University Jena, 07743 Jena, Germany. ; Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany. ; 1] Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany [2] Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Riedberg Campus, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany [3] Institute of Immunology, School of Medicine University of Split, Mestrovicevo setaliste bb, 21 000 Split, Croatia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26040720" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Apoptosis ; Autophagy/*physiology ; Biomarkers/metabolism ; Cell Line ; Endoplasmic Reticulum/chemistry/*metabolism ; Female ; Gene Deletion ; Humans ; Lysosomes/metabolism ; Male ; Membrane Proteins/deficiency/genetics/*metabolism ; Mice ; Microtubule-Associated Proteins/metabolism ; Neoplasm Proteins/deficiency/genetics/*metabolism ; Phagosomes/metabolism ; Protein Binding ; Sensory Receptor Cells/metabolism/pathology
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  • 5
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    Conformational dynamics of a class C G-protein-coupled receptor (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-08-11
    Description: G-protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors in eukaryotes. Crystal structures have provided insight into GPCR interactions with ligands and G proteins, but our understanding of the conformational dynamics of activation is incomplete. Metabotropic glutamate receptors (mGluRs) are dimeric class C GPCRs that modulate neuronal excitability, synaptic plasticity, and serve as drug targets for neurological disorders. A 'clamshell' ligand-binding domain (LBD), which contains the ligand-binding site, is coupled to the transmembrane domain via a cysteine-rich domain, and LBD closure seems to be the first step in activation. Crystal structures of isolated mGluR LBD dimers led to the suggestion that activation also involves a reorientation of the dimer interface from a 'relaxed' to an 'active' state, but the relationship between ligand binding, LBD closure and dimer interface rearrangement in activation remains unclear. Here we use single-molecule fluorescence resonance energy transfer to probe the activation mechanism of full-length mammalian group II mGluRs. We show that the LBDs interconvert between three conformations: resting, activated and a short-lived intermediate state. Orthosteric agonists induce transitions between these conformational states, with efficacy determined by occupancy of the active conformation. Unlike mGluR2, mGluR3 displays basal dynamics, which are Ca(2+)-dependent and lead to basal protein activation. Our results support a general mechanism for the activation of mGluRs in which agonist binding induces closure of the LBDs, followed by dimer interface reorientation. Our experimental strategy should be widely applicable to study conformational dynamics in GPCRs and other membrane proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597782/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597782/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vafabakhsh, Reza -- Levitz, Joshua -- Isacoff, Ehud Y -- 2PN2EY018241/EY/NEI NIH HHS/ -- PN2 EY018241/EY/NEI NIH HHS/ -- England -- Nature. 2015 Aug 27;524(7566):497-501. doi: 10.1038/nature14679. Epub 2015 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA. ; Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720, USA. ; Physical Bioscience Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26258295" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Drug Partial Agonism ; *Fluorescence Resonance Energy Transfer ; Humans ; Ligands ; Models, Biological ; Models, Molecular ; Protein Binding ; Protein Conformation ; Rats ; Receptors, Metabotropic Glutamate/*chemistry/*classification/genetics/metabolism
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  • 6
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    Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-02-18
    Description: The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR-ABL1-driven leukaemia. Axitinib potently inhibited BCR-ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pemovska, Tea -- Johnson, Eric -- Kontro, Mika -- Repasky, Gretchen A -- Chen, Jeffrey -- Wells, Peter -- Cronin, Ciaran N -- McTigue, Michele -- Kallioniemi, Olli -- Porkka, Kimmo -- Murray, Brion W -- Wennerberg, Krister -- England -- Nature. 2015 Mar 5;519(7541):102-5. doi: 10.1038/nature14119. Epub 2015 Feb 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00290 Helsinki, Finland. ; La Jolla Laboratories, Pfizer Worldwide Research &Development, San Diego, California 92121, USA. ; Hematology Research Unit Helsinki, University of Helsinki, and Helsinki University Hospital Comprehensive Cancer Center, Department of Hematology, 00290 Helsinki, Finland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25686603" target="_blank"〉PubMed〈/a〉
    Keywords: Angiogenesis Inhibitors/chemistry/pharmacology/therapeutic use ; Cell Line ; Cell Proliferation/drug effects ; Crystallization ; Crystallography, X-Ray ; Drug Repositioning ; Drug Resistance, Neoplasm/genetics ; Drug Screening Assays, Antitumor ; Fusion Proteins, bcr-abl/*antagonists & inhibitors/*chemistry/genetics/metabolism ; Humans ; Imidazoles/*chemistry/*pharmacology/therapeutic use ; Indazoles/*chemistry/*pharmacology/therapeutic use ; Kidney Neoplasms/drug therapy ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/genetics/metabolism ; Models, Molecular ; Molecular Conformation ; Phosphorylation/drug effects ; Protein Binding ; Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use ; Proto-Oncogene Proteins c-abl/antagonists & ; inhibitors/chemistry/genetics/metabolism ; Vascular Endothelial Growth Factor Receptor-2/antagonists & ; inhibitors/chemistry/metabolism
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  • 7
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    Mechanistic insights into the recycling machine of the SNARE complex (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-01-13
    Description: Evolutionarily conserved SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptors) proteins form a complex that drives membrane fusion in eukaryotes. The ATPase NSF (N-ethylmaleimide sensitive factor), together with SNAPs (soluble NSF attachment protein), disassembles the SNARE complex into its protein components, making individual SNAREs available for subsequent rounds of fusion. Here we report structures of ATP- and ADP-bound NSF, and the NSF/SNAP/SNARE (20S) supercomplex determined by single-particle electron cryomicroscopy at near-atomic to sub-nanometre resolution without imposing symmetry. Large, potentially force-generating, conformational differences exist between ATP- and ADP-bound NSF. The 20S supercomplex exhibits broken symmetry, transitioning from six-fold symmetry of the NSF ATPase domains to pseudo four-fold symmetry of the SNARE complex. SNAPs interact with the SNARE complex with an opposite structural twist, suggesting an unwinding mechanism. The interfaces between NSF, SNAPs, and SNAREs exhibit characteristic electrostatic patterns, suggesting how one NSF/SNAP species can act on many different SNARE complexes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320033/" 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/PMC4320033/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Minglei -- Wu, Shenping -- Zhou, Qiangjun -- Vivona, Sandro -- Cipriano, Daniel J -- Cheng, Yifan -- Brunger, Axel T -- 5-U01AI082051-05/AI/NIAID NIH HHS/ -- P50 GM082250/GM/NIGMS NIH HHS/ -- P50GM082250/GM/NIGMS NIH HHS/ -- R01 GM082893/GM/NIGMS NIH HHS/ -- R01 GM098672/GM/NIGMS NIH HHS/ -- R01GM082893/GM/NIGMS NIH HHS/ -- R01GM098672/GM/NIGMS NIH HHS/ -- R37 MH063105/MH/NIMH NIH HHS/ -- R37MH63105/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Feb 5;518(7537):61-7. doi: 10.1038/nature14148. Epub 2015 Jan 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA. ; Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA. ; 1] Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA [2] Department of Neurology and Neurological Sciences, Department of Structural Biology, Department of Photon Science, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25581794" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Cricetulus ; Cryoelectron Microscopy ; Models, Molecular ; Multiprotein Complexes/*chemistry/*metabolism/ultrastructure ; N-Ethylmaleimide-Sensitive Proteins/chemistry/metabolism/ultrastructure ; Protein Binding ; Protein Structure, Tertiary ; Rats ; SNARE Proteins/*chemistry/*metabolism/ultrastructure ; Soluble N-Ethylmaleimide-Sensitive Factor Attachment ; Proteins/chemistry/metabolism/ultrastructure
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  • 8
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    ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-02-18
    Description: Autophagy, an important catabolic pathway implicated in a broad spectrum of human diseases, begins by forming double membrane autophagosomes that engulf cytosolic cargo and ends by fusing autophagosomes with lysosomes for degradation. Membrane fusion activity is required for early biogenesis of autophagosomes and late degradation in lysosomes. However, the key regulatory mechanisms of autophagic membrane tethering and fusion remain largely unknown. Here we report that ATG14 (also known as beclin-1-associated autophagy-related key regulator (Barkor) or ATG14L), an essential autophagy-specific regulator of the class III phosphatidylinositol 3-kinase complex, promotes membrane tethering of protein-free liposomes, and enhances hemifusion and full fusion of proteoliposomes reconstituted with the target (t)-SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) syntaxin 17 (STX17) and SNAP29, and the vesicle (v)-SNARE VAMP8 (vesicle-associated membrane protein 8). ATG14 binds to the SNARE core domain of STX17 through its coiled-coil domain, and stabilizes the STX17-SNAP29 binary t-SNARE complex on autophagosomes. The STX17 binding, membrane tethering and fusion-enhancing activities of ATG14 require its homo-oligomerization by cysteine repeats. In ATG14 homo-oligomerization-defective cells, autophagosomes still efficiently form but their fusion with endolysosomes is blocked. Recombinant ATG14 homo-oligomerization mutants also completely lose their ability to promote membrane tethering and to enhance SNARE-mediated fusion in vitro. Taken together, our data suggest an autophagy-specific membrane fusion mechanism in which oligomeric ATG14 directly binds to STX17-SNAP29 binary t-SNARE complex on autophagosomes and primes it for VAMP8 interaction to promote autophagosome-endolysosome fusion.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442024/" 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/PMC4442024/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Diao, Jiajie -- Liu, Rong -- Rong, Yueguang -- Zhao, Minglei -- Zhang, Jing -- Lai, Ying -- Zhou, Qiangjun -- Wilz, Livia M -- Li, Jianxu -- Vivona, Sandro -- Pfuetzner, Richard A -- Brunger, Axel T -- Zhong, Qing -- 5P30CA142543/CA/NCI NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- R01 CA133228/CA/NCI NIH HHS/ -- R01 R37-MH63105/MH/NIMH NIH HHS/ -- R37 MH063105/MH/NIMH NIH HHS/ -- T32 GM007232/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Apr 23;520(7548):563-6. doi: 10.1038/nature14147. Epub 2015 Feb 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular and Cellular Physiology, Stanford University, Stanford, California 94305, USA [2] Department of Structural Biology, Stanford University, Stanford, California 94305, USA [3] Department of Photon Science, Stanford University, Stanford, California 94305, USA [4] Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305, USA [5] Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA. ; 1] Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [3] College of Food Science &Nutritional Engineering, China Agricultural University, Beijing 100083, China. ; 1] Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Division of Biochemistry, Biophysics and Structural Biology, Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25686604" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Vesicular Transport/*chemistry/*metabolism ; *Autophagy ; Endosomes/*metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Lysosomes/*metabolism ; *Membrane Fusion ; Phagosomes/chemistry/*metabolism ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Qa-SNARE Proteins/metabolism ; Qb-SNARE Proteins/metabolism ; Qc-SNARE Proteins/metabolism ; R-SNARE Proteins/metabolism ; SNARE Proteins/chemistry/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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    Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-09-04
    Description: TP53 (which encodes p53 protein) is the most frequently mutated gene among all human cancers. Prevalent p53 missense mutations abrogate its tumour suppressive function and lead to a 'gain-of-function' (GOF) that promotes cancer. Here we show that p53 GOF mutants bind to and upregulate chromatin regulatory genes, including the methyltransferases MLL1 (also known as KMT2A), MLL2 (also known as KMT2D), and acetyltransferase MOZ (also known as KAT6A or MYST3), resulting in genome-wide increases of histone methylation and acetylation. Analysis of The Cancer Genome Atlas shows specific upregulation of MLL1, MLL2, and MOZ in p53 GOF patient-derived tumours, but not in wild-type p53 or p53 null tumours. Cancer cell proliferation is markedly lowered by genetic knockdown of MLL1 or by pharmacological inhibition of the MLL1 methyltransferase complex. Our study reveals a novel chromatin mechanism underlying the progression of tumours with GOF p53, and suggests new possibilities for designing combinatorial chromatin-based therapies for treating individual cancers driven by prevalent GOF p53 mutations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568559/" 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/PMC4568559/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhu, Jiajun -- Sammons, Morgan A -- Donahue, Greg -- Dou, Zhixun -- Vedadi, Masoud -- Getlik, Matthaus -- Barsyte-Lovejoy, Dalia -- Al-awar, Rima -- Katona, Bryson W -- Shilatifard, Ali -- Huang, Jing -- Hua, Xianxin -- Arrowsmith, Cheryl H -- Berger, Shelley L -- 092809/Z/10/Z/Wellcome Trust/United Kingdom -- P30 ES013508/ES/NIEHS NIH HHS/ -- R01 CA078831/CA/NCI NIH HHS/ -- R01 GM069905/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Sep 10;525(7568):206-11. doi: 10.1038/nature15251. Epub 2015 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Biomedical Graduate Studies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada. ; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada. ; Abramson Family Cancer Research Institute, Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 E. Superior Street, Chicago, Illinois 60611, USA. ; Cancer and Stem Cell Epigenetics, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA. ; Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C4, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26331536" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Cell Line, Tumor ; Cell Proliferation/genetics ; Chromatin/chemistry/*genetics/*metabolism ; Female ; Genes, Tumor Suppressor ; Genome, Human/genetics ; Histone Acetyltransferases/metabolism ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/chemistry/metabolism ; Humans ; Male ; Mice ; Mutant Proteins/genetics/metabolism ; Mutation/*genetics ; Myeloid-Lymphoid Leukemia Protein/metabolism ; Neoplasms/*genetics/metabolism/*pathology ; Phenotype ; Protein Binding ; Protein Processing, Post-Translational ; Tumor Suppressor Protein p53/*genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Competition between DNA methylation and transcription factors determines binding of NRF1 (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-12-18
    Description: Eukaryotic transcription factors (TFs) are key determinants of gene activity, yet they bind only a fraction of their corresponding DNA sequence motifs in any given cell type. Chromatin has the potential to restrict accessibility of binding sites; however, in which context chromatin states are instructive for TF binding remains mainly unknown. To explore the contribution of DNA methylation to constrained TF binding, we mapped DNase-I-hypersensitive sites in murine stem cells in the presence and absence of DNA methylation. Methylation-restricted sites are enriched for TF motifs containing CpGs, especially for those of NRF1. In fact, the TF NRF1 occupies several thousand additional sites in the unmethylated genome, resulting in increased transcription. Restoring de novo methyltransferase activity initiates remethylation at these sites and outcompetes NRF1 binding. This suggests that binding of DNA-methylation-sensitive TFs relies on additional determinants to induce local hypomethylation. In support of this model, removal of neighbouring motifs in cis or of a TF in trans causes local hypermethylation and subsequent loss of NRF1 binding. This competition between DNA methylation and TFs in vivo reveals a case of cooperativity between TFs that acts indirectly via DNA methylation. Methylation removal by methylation-insensitive factors enables occupancy of methylation-sensitive factors, a principle that rationalizes hypomethylation of regulatory regions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Domcke, Silvia -- Bardet, Anais Flore -- Adrian Ginno, Paul -- Hartl, Dominik -- Burger, Lukas -- Schubeler, Dirk -- England -- Nature. 2015 Dec 24;528(7583):575-9. doi: 10.1038/nature16462. Epub 2015 Dec 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH 4058 Basel, Switzerland. ; University of Basel, Faculty of Sciences, Petersplatz 1, CH 4003 Basel, Switzerland. ; Swiss Institute of Bioinformatics, Maulbeerstrasse 66, CH 4058 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26675734" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Binding, Competitive ; Cells, Cultured ; Chromatin/chemistry/genetics/*metabolism ; *DNA Methylation ; Deoxyribonuclease I/metabolism ; Genome/genetics ; Humans ; Mice ; Mouse Embryonic Stem Cells/metabolism ; Nuclear Respiratory Factor 1/*metabolism ; Protein Binding ; Transcription Factors/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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