ArticleThe Journal of biological chemistry2012
The role of the N-domain in the ATPase activity of the mammalian AAA ATPase p97/VCP.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers.
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Who cites it
85 citing papers in PubMed, 121 citations in OpenAlex.
- The Autophagic Interaction Between p97/VCP and ABP Protein Expressions in Sertoli Cell Line: the Effects of Chloroquine and Rapamycin.Reproductive sciences (Thousand Oaks, Calif.) · 2026Article
- The long road to diagnosis: recessive PMPCB deficiency hidden behind a dominant familial VCP defect.Molecular genetics and metabolism reports · 2026Article
- Npl4 decodes polyubiquitin length and gates D1-D2 coupling in human VCP/p97.Research square · 2026Article
- ASPL-driven subunit exchange remodels VCP/p97 hexamers and is impaired by a multisystem proteinopathy mutation.bioRxiv : the preprint server for biology · 2026Article
- Npl4 decodes polyubiquitin length and gates D1-D2 coupling in human VCP/p97.bioRxiv : the preprint server for biology · 2026Article
- Deposition of CENP-ACse4 is enhanced by mutations in the AAA+ ATPase domain of ATAD2Yta7.Genetics · 2026Article
- Utilization of CoRDS registry to monitor quality of life in patients with VCP multisystem proteinopathy.Orphanet journal of rare diseases · 2025Article
- Elevated VCP ATPase Activity Correlates With Disease Onset in Multisystem Proteinopathy-1.Neurology. Genetics · 2024Article
- Mechanism of allosteric inhibition of human p97/VCP ATPase and its disease mutant by triazole inhibitors.Communications chemistry · 2024Article
- Valosin-Containing Protein (VCP): A Review of Its Diverse Molecular Functions and Clinical Phenotypes.International journal of molecular sciences · 2024Review
- Valosin-Containing Protein (VCP)/p97 Oligomerization.Sub-cellular biochemistry · 2024Review
- Clinical Classification of Variants in the Valosin-Containing Protein Gene Associated With Multisystem Proteinopathy.Neurology. Genetics · 2023Article
- Novel Variants in theGenes · 2023Article
- Article
- Compounds activating VCP D1 ATPase enhance both autophagic and proteasomal neurotoxic protein clearance.Nature communications · 2022Article
- A clinicopathologic study of malignancy in VCP-associated multisystem proteinopathy.Orphanet journal of rare diseases · 2022Article
- Autophagy Dysfunction in ALS: from Transport to Protein Degradation.Journal of molecular neuroscience : MN · 2022Review
- AAA-ATPase valosin-containing protein binds the transcription factor SREBP1 and promotes its proteolytic activation by rhomboid protease RHBDL4.The Journal of biological chemistry · 2022Article
- Cryo-EM structures of human p97 double hexamer capture potentiated ATPase-competent state.Cell discovery · 2022Article
- Article
25 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
p97/valosin-containing protein (VCP) is a type II ATPase associated with various cellular activities that forms a homohexamer with each protomer containing an N-terminal domain (N-domain); two ATPase domains, D1 and D2; and a disordered C-terminal region. Little is known about the role of the N-domain or the C-terminal region in the p97 ATPase cycle. In the p97-associated human disease inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia, the majority of missense mutations are located at the N-domain D1 interface. Structure-based predictions suggest that such mutations affect the interaction of the N-domain with D1. Here we have tested ten major inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia-linked mutants for ATPase activity and found that all have increased activity over the wild type, with one mutant, p97(A232E), having three times higher activity. Further mutagenesis of p97(A232E) shows that the increase in ATPase activity is mediated through D2 and requires both the N-domain and a flexible ND1 linker. A disulfide mutation that locks the N-domain to D1 in a coplanar position reversibly abrogates ATPase activity. A cryo-EM reconstruction of p97(A232E) suggests that the N-domains are flexible. Removal of the C-terminal region also reduces ATPase activity. Taken together, our data suggest that the conformation of the N-domain in relation to the D1-D2 hexamer is directly linked to ATP hydrolysis and that the C-terminal region is required for hexamer stability. This leads us to propose a model where the N-domain adopts either of two conformations: a flexible conformation compatible with ATP hydrolysis or a coplanar conformation that is inactive.
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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.