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| | ==Structure of Beclin1-UVRAG coiled coil domain complex== | | ==Structure of Beclin1-UVRAG coiled coil domain complex== |
| - | <StructureSection load='5yr0' size='340' side='right' caption='[[5yr0]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='5yr0' size='340' side='right'caption='[[5yr0]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5yr0]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5YR0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5YR0 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5yr0]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5YR0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5YR0 FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Becn1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice]), Uvrag, Uvrag1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5yr0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5yr0 OCA], [http://pdbe.org/5yr0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5yr0 RCSB], [http://www.ebi.ac.uk/pdbsum/5yr0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5yr0 ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5yr0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5yr0 OCA], [https://pdbe.org/5yr0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5yr0 RCSB], [https://www.ebi.ac.uk/pdbsum/5yr0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5yr0 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/BECN1_MOUSE BECN1_MOUSE]] Plays a central role in autophagy. Required for the abcission step in cytokinesis. May play a role in antiviral host defense.<ref>PMID:10604474</ref> <ref>PMID:12372286</ref> <ref>PMID:19270693</ref> [[http://www.uniprot.org/uniprot/UVRAG_MOUSE UVRAG_MOUSE]] Versatile protein that is involved in regulation of different cellular pathways implicated in membrane trafficking. Involved in regulation of the COPI-dependent retrograde transport from Golgi and the endoplasmic reticulum by associating with the NRZ complex; the function is dependent on its binding to phosphatidylinositol 3-phosphate (PtdIns(3)P). During autophagy acts as regulatory subunit of the alternative PI3K complex II (PI3KC3-C2) that mediates formation of phosphatidylinositol 3-phosphate and is believed to be involved in maturation of autophagosomes and endocytosis. Activates lipid kinase activity of PIK3C3. Involved in the regulation of degradative endocytic trafficking and cytokinesis, and in regulation of ATG9A transport from the Golgi to the autophagosome; the functions seems to implicate its association with PI3KC3-C2. Involved in maturation of autophagosomes and degradative endocytic trafficking independently of BECN1 but depending on its association with a class C Vps complex (possibly the HOPS complex); the association is also proposed to promote autophagosome recruitment and activation of Rab7 and endosome-endosome fusion events. Enhances class C Vps complex (possibly HOPS complex) association with a SNARE complex and promotes fusogenic SNARE complex formation during late endocytic membrane fusion. In case of negative-strand RNA virus infection is required for efficient virus entry, promotes endocytic transport of virions and is implicated in a VAMP8-specific fusogenic SNARE complex assembly (By similarity).[UniProtKB:Q9P2Y5] Involved in maintaining chromosomal stability. Promotes DNA double-strand break (DSB) repair by association with DNA-dependent protein kinase complex DNA-PK and activating it in non-homologous end joining (NHEJ). Required for centrosome stability and proper chromosome segregation (By similarity).[UniProtKB:Q9P2Y5] | + | [https://www.uniprot.org/uniprot/BECN1_MOUSE BECN1_MOUSE] Plays a central role in autophagy. Required for the abcission step in cytokinesis. May play a role in antiviral host defense.<ref>PMID:10604474</ref> <ref>PMID:12372286</ref> <ref>PMID:19270693</ref> |
| - | <div style="background-color:#fffaf0;">
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| - | == Publication Abstract from PubMed ==
| + | |
| - | The Beclin 1-Vps34 complex, known as "mammalian class III PI3K," plays essential roles in membrane-mediated transport processes including autophagy and endosomal trafficking. Beclin 1 acts as a scaffolding molecule for the complex and readily transits from its metastable homodimeric state to interact with key modulators such as Atg14L or UVRAG and form functionally distinct Atg14L/UVRAG-containing Beclin 1-Vps34 subcomplexes. The Beclin 1-Atg14L/UVRAG interaction relies critically on their coiled-coil domains, but the molecular mechanism remains poorly understood. We determined the crystal structure of Beclin 1-UVRAG coiled-coil complex and identified a strengthened interface with both hydrophobic pairings and electrostatically complementary interactions. This structure explains why the Beclin 1-UVRAG interaction is more potent than the metastable Beclin 1 homodimer. Potent Beclin 1-UVRAG interaction is functionally significant because it renders UVRAG more competitive than Atg14L in Beclin 1 binding and is critical for promoting endolysosomal trafficking. UVRAG coiled-coil mutants with weakened Beclin 1 binding do not outcompete Atg14L and fail to promote endolysosomal degradation of the EGF receptor (EGFR). We designed all-hydrocarbon stapled peptides that specifically targeted the C-terminal part of the Beclin 1 coiled-coil domain to interfere with its homodimerization. One such peptide reduced Beclin 1 self-association, promoted Beclin 1-Atg14L/UVRAG interaction, increased autophagic flux, and enhanced EGFR degradation. Our results demonstrate that the targeting Beclin 1 coiled-coil domain with designed peptides to induce the redistribution of Beclin 1 among its self-associated form or Atg14L/UVRAG-containing complexes enhances both autophagy and endolysosomal trafficking.
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| - | Targeting the potent Beclin 1-UVRAG coiled-coil interaction with designed peptides enhances autophagy and endolysosomal trafficking.,Wu S, He Y, Qiu X, Yang W, Liu W, Li X, Li Y, Shen HM, Wang R, Yue Z, Zhao Y Proc Natl Acad Sci U S A. 2018 Jun 4. pii: 1721173115. doi:, 10.1073/pnas.1721173115. PMID:29866835<ref>PMID:29866835</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 5yr0" style="background-color:#fffaf0;"></div>
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| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Large Structures]] |
| - | [[Category: He, Y]] | + | [[Category: Mus musculus]] |
| - | [[Category: Pan, X]] | + | [[Category: He Y]] |
| - | [[Category: Zhao, Y]]
| + | [[Category: Pan X]] |
| - | [[Category: Autophagy regulator]] | + | [[Category: Zhao Y]] |
| - | [[Category: Endocytosis]] | + | |
