ArticleProceedings of the National Academy of Sciences of the United States of America2015
Altered cofactor regulation with disease-associated p97/VCP mutations.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed, 111 citations in OpenAlex.
- FAF1 and FAF2 enhance unfolding by p97-UFD1-NPL4 complex enabling rational design of p97 activators.The EMBO journal · 2026Article
- Npl4 decodes polyubiquitin length and gates D1-D2 coupling in human VCP/p97.Research square · 2026Article
- Npl4 decodes polyubiquitin length and gates D1-D2 coupling in human VCP/p97.bioRxiv : the preprint server for biology · 2026Article
- The VCPKMT-VCP-HDAC1 axis inhibits colorectal cancer by conferring sensitivity to ferroptosis.Cancer cell international · 2025Article
- Host AAA-ATPase VCP/p97 lyses ubiquitinated intracellular bacteria as an innate antimicrobial defence.Nature microbiology · 2025Article
- VCP regulates early tau seed amplification via specific cofactors.Molecular neurodegeneration · 2025Article
- Loss of function of VCP/TER94 causes neurodegeneration.Disease models & mechanisms · 2024Article
- Mechanism of allosteric inhibition of human p97/VCP ATPase and its disease mutant by triazole inhibitors.Communications chemistry · 2024Article
- Localized K63 ubiquitin signaling is regulated by VCP/p97 during oxidative stress.bioRxiv : the preprint server for biology · 2024Article
- Allosteric activation of VCP, an AAA unfoldase, by small molecule mimicry.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- VCP regulates early tau seed amplification via specific cofactors.Research square · 2024Article
- p37 regulates VCP/p97 shuttling and functions in the nucleus and cytosol.Science advances · 2024Article
- Bidirectional substrate shuttling between the 26S proteasome and the Cdc48 ATPase promotes protein degradation.Molecular cell · 2024Article
- UBXN1 maintains ER proteostasis and represses UPR activation by modulating translation.EMBO reports · 2024Article
- Golgi defect as a major contributor to lysosomal dysfunction.Frontiers in cell and developmental biology · 2024Review
- Structural insights of the p97/VCP AAA+ ATPase: How adapter interactions coordinate diverse cellular functionality.The Journal of biological chemistry · 2023Review
- Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases.Molecular neurodegeneration · 2023Review
- Molecular Mechanisms Driving and Regulating the AAA+ ATPase VCP/p97, an Important Therapeutic Target for Treating Cancer, Neurological and Infectious Diseases.Biomolecules · 2023Review
- Common Markers and Small Molecule Inhibitors in Golgi Studies.Methods in molecular biology (Clifton, N.J.) · 2023Article
- In silico prediction, characterization, docking studies and molecular dynamics simulation of human p97 in complex with p37 cofactor.BMC molecular and cell biology · 2022Article
9 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 2 countries.
Funding
Abstract
Dominant mutations in p97/VCP (valosin-containing protein) cause a rare multisystem degenerative disease with varied phenotypes that include inclusion body myopathy, Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis. p97 disease mutants have altered N-domain conformations, elevated ATPase activity, and altered cofactor association. We have now discovered a previously unidentified disease-relevant functional property of p97 by identifying how the cofactors p37 and p47 regulate p97 ATPase activity. We define p37 as, to our knowledge, the first known p97-activating cofactor, which enhances the catalytic efficiency (kcat/Km) of p97 by 11-fold. Whereas both p37 and p47 decrease the Km of ATP in p97, p37 increases the kcat of p97. In contrast, regulation by p47 is biphasic, with decreased kcat at low levels but increased kcat at higher levels. By deleting a region of p47 that lacks homology to p37 (amino acids 69-92), we changed p47 from an inhibitory cofactor to an activating cofactor, similar to p37. Our data suggest that cofactors regulate p97 ATPase activity by binding to the N domain. Induced conformation changes affect ADP/ATP binding at the D1 domain, which in turn controls ATPase cycling. Most importantly, we found that the D2 domain of disease mutants failed to be activated by p37 or p47. Our results show that cofactors play a critical role in controlling p97 ATPase activity, and suggest that lack of cofactor-regulated communication may contribute to p97-associated disease pathogenesis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.