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| <StructureSection load='7vcs' size='340' side='right'caption='[[7vcs]], [[Resolution|resolution]] 3.32Å' scene=''> | | <StructureSection load='7vcs' size='340' side='right'caption='[[7vcs]], [[Resolution|resolution]] 3.32Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[7vcs]] is a 12 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VCS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VCS FirstGlance]. <br> | | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VCS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VCS FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AGS:PHOSPHOTHIOPHOSPHORIC+ACID-ADENYLATE+ESTER'>AGS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.32Å</td></tr> |
| <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Vesicle-fusing_ATPase Vesicle-fusing ATPase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.4.6 3.6.4.6] </span></td></tr> | | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AGS:PHOSPHOTHIOPHOSPHORIC+ACID-ADENYLATE+ESTER'>AGS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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=7vcs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vcs OCA], [https://pdbe.org/7vcs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vcs RCSB], [https://www.ebi.ac.uk/pdbsum/7vcs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vcs 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=7vcs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vcs OCA], [https://pdbe.org/7vcs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vcs RCSB], [https://www.ebi.ac.uk/pdbsum/7vcs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vcs ProSAT]</span></td></tr> |
| </table> | | </table> |
| == Disease ==
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| [[https://www.uniprot.org/uniprot/TERA_HUMAN TERA_HUMAN]] Defects in VCP are the cause of inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD) [MIM:[https://omim.org/entry/167320 167320]]; also known as muscular dystrophy, limb-girdle, with Paget disease of bone or pagetoid amyotrophic lateral sclerosis or pagetoid neuroskeletal syndrome or lower motor neuron degeneration with Paget-like bone disease. IBMPFD features adult-onset proximal and distal muscle weakness (clinically resembling limb girdle muscular dystrophy), early-onset Paget disease of bone in most cases and premature frontotemporal dementia.<ref>PMID:20512113</ref> <ref>PMID:15034582</ref> <ref>PMID:15732117</ref> <ref>PMID:16247064</ref> <ref>PMID:16321991</ref> Defects in VCP are the cause of amyotrophic lateral sclerosis type 14 with or without frontotemporal dementia (ALS14) [MIM:[https://omim.org/entry/613954 613954]]. ALS14 is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Patients with ALS14 may develop frontotemporal dementia.<ref>PMID:21145000</ref>
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| == Function ==
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| [[https://www.uniprot.org/uniprot/TERA_HUMAN TERA_HUMAN]] Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. Involved in the formation of the transitional endoplasmic reticulum (tER). The transfer of membranes from the endoplasmic reticulum to the Golgi apparatus occurs via 50-70 nm transition vesicles which derive from part-rough, part-smooth transitional elements of the endoplasmic reticulum (tER). Vesicle budding from the tER is an ATP-dependent process. The ternary complex containing UFD1L, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1L-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. Regulates E3 ubiquitin-protein ligase activity of RNF19A (By similarity). Component of the VCP/p97-AMFR/gp78 complex that participates in the final step of the sterol-mediated ubiquitination and endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Also involved in DNA damage response: recruited to double-strand breaks (DSBs) sites in a RNF8- and RNF168-dependent manner and promotes the recruitment of TP53BP1 at DNA damage sites. Recruited to stalled replication forks by SPRTN: may act by mediating extraction of DNA polymerase eta (POLH) to prevent excessive translesion DNA synthesis and limit the incidence of mutations induced by DNA damage.<ref>PMID:15456787</ref> <ref>PMID:16168377</ref> <ref>PMID:22020440</ref> <ref>PMID:22120668</ref> <ref>PMID:22607976</ref> <ref>PMID:23042607</ref> <ref>PMID:23042605</ref>
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| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| The conserved ATPase p97 (Cdc48 in yeast) and adaptors mediate diverse cellular processes through unfolding polyubiquitinated proteins and extracting them from macromolecular assemblies and membranes for disaggregation and degradation. The tandem ATPase domains (D1 and D2) of the p97/Cdc48 hexamer form stacked rings. p97/Cdc48 can unfold substrates by threading them through the central pore. The pore loops critical for substrate unfolding are, however, not well-ordered in substrate-free p97/Cdc48 conformations. How p97/Cdc48 organizes its pore loops for substrate engagement is unclear. Here we show that p97/Cdc48 can form double hexamers (DH) connected through the D2 ring. Cryo-EM structures of p97 DH reveal an ATPase-competent conformation with ordered pore loops. The C-terminal extension (CTE) links neighboring D2s in each hexamer and expands the central pore of the D2 ring. Mutations of Cdc48 CTE abolish substrate unfolding. We propose that the p97/Cdc48 DH captures a potentiated state poised for substrate engagement.
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| Cryo-EM structures of human p97 double hexamer capture potentiated ATPase-competent state.,Gao H, Li F, Ji Z, Shi Z, Li Y, Yu H Cell Discov. 2022 Feb 22;8(1):19. doi: 10.1038/s41421-022-00379-1. PMID:35190543<ref>PMID:35190543</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 7vcs" style="background-color:#fffaf0;"></div>
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| == References ==
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| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Vesicle-fusing ATPase]]
| | [[Category: Gao H]] |
| [[Category: Gao, H]] | | [[Category: Li F]] |
| [[Category: Li, F]] | | [[Category: Li Y]] |
| [[Category: Li, Y]] | | [[Category: Shi Z]] |
| [[Category: Shi, Z]] | | [[Category: Yu H]] |
| [[Category: Yu, H]] | |
| [[Category: Aaa+ atpase]]
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| [[Category: Cell cycle]]
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| [[Category: Hydrolase]]
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| [[Category: Unfoldase]]
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