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| Line 8: |
Line 8: |
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8ooi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ooi OCA], [https://pdbe.org/8ooi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ooi RCSB], [https://www.ebi.ac.uk/pdbsum/8ooi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ooi 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=8ooi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ooi OCA], [https://pdbe.org/8ooi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ooi RCSB], [https://www.ebi.ac.uk/pdbsum/8ooi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ooi ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Disease == | + | <div style="background-color:#fffaf0;"> |
| - | [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>
| + | == Publication Abstract from PubMed == |
| - | == Function ==
| + | The human enzyme p97 regulates various cellular pathways by unfolding hundreds of protein substrates in an ATP-dependent manner, making it an essential component of protein homeostasis and an impactful pharmacological target. The hexameric complex undergoes substantial conformational changes throughout its catalytic cycle. Here we elucidate the molecular motions that occur at the active site in the temporal window immediately before and after ATP hydrolysis by merging cryo-EM, NMR spectroscopy and molecular dynamics simulations. p97 populates a metastable reaction intermediate, the ADP.P(i) state, which is poised between hydrolysis and product release. Detailed snapshots reveal that the active site is finely tuned to trap and eventually discharge the cleaved phosphate. Signalling pathways originating at the active site coordinate the action of the hexamer subunits and couple hydrolysis with allosteric conformational changes. Our multidisciplinary approach enables a glimpse into the sophisticated spatial and temporal orchestration of ATP handling by a prototype AAA+ protein. |
| - | [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>
| + | |
| | + | Characterizing ATP processing by the AAA+ protein p97 at the atomic level.,Shein M, Hitzenberger M, Cheng TC, Rout SR, Leitl KD, Sato Y, Zacharias M, Sakata E, Schutz AK Nat Chem. 2024 Mar;16(3):363-372. doi: 10.1038/s41557-024-01440-0. Epub 2024 Feb , 7. PMID:38326645<ref>PMID:38326645</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 8ooi" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| Structural highlights
8ooi is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | Electron Microscopy, Resolution 2.61Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Publication Abstract from PubMed
The human enzyme p97 regulates various cellular pathways by unfolding hundreds of protein substrates in an ATP-dependent manner, making it an essential component of protein homeostasis and an impactful pharmacological target. The hexameric complex undergoes substantial conformational changes throughout its catalytic cycle. Here we elucidate the molecular motions that occur at the active site in the temporal window immediately before and after ATP hydrolysis by merging cryo-EM, NMR spectroscopy and molecular dynamics simulations. p97 populates a metastable reaction intermediate, the ADP.P(i) state, which is poised between hydrolysis and product release. Detailed snapshots reveal that the active site is finely tuned to trap and eventually discharge the cleaved phosphate. Signalling pathways originating at the active site coordinate the action of the hexamer subunits and couple hydrolysis with allosteric conformational changes. Our multidisciplinary approach enables a glimpse into the sophisticated spatial and temporal orchestration of ATP handling by a prototype AAA+ protein.
Characterizing ATP processing by the AAA+ protein p97 at the atomic level.,Shein M, Hitzenberger M, Cheng TC, Rout SR, Leitl KD, Sato Y, Zacharias M, Sakata E, Schutz AK Nat Chem. 2024 Mar;16(3):363-372. doi: 10.1038/s41557-024-01440-0. Epub 2024 Feb , 7. PMID:38326645[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Shein M, Hitzenberger M, Cheng TC, Rout SR, Leitl KD, Sato Y, Zacharias M, Sakata E, Schütz AK. Characterizing ATP processing by the AAA+ protein p97 at the atomic level. Nat Chem. 2024 Mar;16(3):363-372. PMID:38326645 doi:10.1038/s41557-024-01440-0
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