ArticleProceedings of the National Academy of Sciences of the United States of America2017
Exploiting conformational plasticity in the AAA+ protein VCP/p97 to modify function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 45 citations in OpenAlex.
- The vacuolar tauopathy-associated mutation D395G confers redox sensitivity to p97/VCP.bioRxiv : the preprint server for biology · 2026Article
- Molecular Mechanism of ATP Hydrolysis Catalyzed by p97: A QM/MM Study.Journal of chemical theory and computation · 2025Article
- Allosteric regulation of proteolytic machines unveiled by the synergy between cryo-EM and solution NMR spectroscopy.The Biochemical journal · 2025Review
- 2024 VCP International Conference: Exploring multi-disciplinary approaches from basic science of valosin containing protein, an AAA+ ATPase protein, to the therapeutic advancement for VCP-associated multisystem proteinopathy.Neurobiology of disease · 2025Review
- Dynamic sampling of a surveillance state enables DNA proofreading by Cas9.Cell chemical biology · 2025Article
- Mechanism of allosteric inhibition of human p97/VCP ATPase and its disease mutant by triazole inhibitors.Communications chemistry · 2024Article
- Conserved proline residues prevent dimerization and aggregation in the β-lactamase BlaC.Protein science : a publication of the Protein Society · 2024Article
- Analysis of the Conformational Landscape of the N-Domains of the AAA ATPase p97: Disentangling the Continuous Conformational Variability in Partially Symmetrical Complexes.International journal of molecular sciences · 2024Article
- The p97/VCP adaptor UBXD1 drives AAA+ remodeling and ring opening through multi-domain tethered interactions.Nature structural & molecular biology · 2023Article
- Amplifying the Heat Shock Response Ameliorates ALS and FTD Pathology in Mouse and Human Models.Molecular neurobiology · 2023Article
- Structural insights of the p97/VCP AAA+ ATPase: How adapter interactions coordinate diverse cellular functionality.The Journal of biological chemistry · 2023Review
- Molecular Mechanisms Driving and Regulating the AAA+ ATPase VCP/p97, an Important Therapeutic Target for Treating Cancer, Neurological and Infectious Diseases.Biomolecules · 2023Review
- An NMR portrait of functional and dysfunctional allosteric cooperativity in cAMP-dependent protein kinase A.FEBS letters · 2023Review
- An Updated Review and Meta Analysis of Lipoprotein Glomerulopathy.Frontiers in medicine · 2022Review
- The Role of VCP Mutations in the Spectrum of Amyotrophic Lateral Sclerosis-Frontotemporal Dementia.Frontiers in neurology · 2022Review
- Probing allosteric interactions in homo-oligomeric molecular machines using solution NMR spectroscopy.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Theoretical classification of exchange geometries from the perspective of NMR relaxation dispersion.Journal of magnetic resonance (San Diego, Calif. : 1997) · 2021Article
- The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Proteostasis Factors.Journal of neuropathology and experimental neurology · 2021Review
- Entropic Inhibition: How the Activity of a AAA+ Machine Is Modulated by Its Substrate-Binding Domain.ACS chemical biology · 2021Article
- An intrinsically disordered motif regulates the interaction between the p47 adaptor and the p97 AAA+ ATPase.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
p97/VCP, a member of the AAA+ (ATPases associated with diverse cellular activities) family of proteins, is implicated in the etiology of a group of degenerative diseases affecting bone and muscle tissue as well as the central nervous system. Methyl-TROSY-based NMR studies have previously revealed how disease-causing mutations deregulate a subtle dynamic conformational equilibrium involving the N-terminal domain (NTD) with implications for the binding of certain adaptors, providing insight into how disease mutations lead to abnormal function. Herein the conformational plasticity of the p97 system is explored in an attempt to identify hotspots that can serve as targets for restoring function in disease mutants by shifting the position of the NTD back to its wild-type location. Although p97 is overall robust with respect to extensive mutagenesis throughout the protein involving conservative substitutions of hydrophobic residues, key positions have been identified that alter the NTD equilibrium; these lie in specific regions that localize to the interface between the NTD and the D1 nucleotide-binding domain of the complex. Notably, for a severe disease mutant involving an R155C substitution the NTD equilibrium can be shifted back to its wild-type position by mutation at a secondary site with restoration of wild-type two-pronged binding of the UBXD1 adaptor protein that is impaired in disease; this underlies the potential for recovering function by targeting p97 disease mutants with drug molecules.
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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.