ArticleProceedings of the National Academy of Sciences of the United States of America2019
Cooperative subunit dynamics modulate p97 function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 41 citations in OpenAlex.
- 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
- Allosteric regulation of proteolytic machines unveiled by the synergy between cryo-EM and solution NMR spectroscopy.The Biochemical journal · 2025Review
- Mechanism of allosteric inhibition of human p97/VCP ATPase and its disease mutant by triazole inhibitors.Communications chemistry · 2024Article
- Article
- The p97/VCP adaptor UBXD1 drives AAA+ remodeling and ring opening through multi-domain tethered interactions.Nature structural & molecular biology · 2023Article
- Structure of the peroxisomal Pex1/Pex6 ATPase complex bound to a substrate.Nature communications · 2023Article
- Molecular Mechanisms Driving and Regulating the AAA+ ATPase VCP/p97, an Important Therapeutic Target for Treating Cancer, Neurological and Infectious Diseases.Biomolecules · 2023Review
- The functional importance of VCP to maintaining cellular protein homeostasis.Biochemical Society transactions · 2022Review
- Thermodynamic coupling between neighboring binding sites in homo-oligomeric ligand sensing proteins from mass resolved ligand-dependent population distributions.Protein science : a publication of the Protein Society · 2022Article
- Active conformation of the p97-p47 unfoldase complex.Nature communications · 2022Article
- 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
- Dissecting the role of interprotomer cooperativity in the activation of oligomeric high-temperature requirement A2 protein.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes.International journal of molecular sciences · 2021Article
- The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Proteostasis Factors.Journal of neuropathology and experimental neurology · 2021Review
- Molecular basis for the allosteric activation mechanism of the heterodimeric imidazole glycerol phosphate synthase complex.Nature communications · 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
- Allosteric pluripotency as revealed by protein kinase A.Science advances · 2020Article
- AAA+ ATPases in Protein Degradation: Structures, Functions and Mechanisms.Biomolecules · 2020Review
- Exploring long-range cooperativity in the 20S proteasome core particle fromProceedings of the National Academy of Sciences of the United States of America · 2020Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
p97 is an essential hexameric AAA+ ATPase involved in a wide range of cellular processes. Mutations in the enzyme are implicated in the etiology of an autosomal dominant neurological disease in which patients are heterozygous with respect to p97 alleles, containing one copy each of WT and disease-causing mutant genes, so that, in vivo, p97 molecules can be heterogeneous in subunit composition. Studies of p97 have, however, focused on homohexameric constructs, where protomers are either entirely WT or contain a disease-causing mutation, showing that for WT p97, the N-terminal domain (NTD) of each subunit can exist in either a down (ADP) or up (ATP) conformation. NMR studies establish that, in the ADP-bound state, the up/down NTD equilibrium shifts progressively toward the up conformation as a function of disease mutant severity. To understand NTD functional dynamics in biologically relevant p97 heterohexamers comprising both WT and disease-causing mutant subunits, we performed a methyl-transverse relaxation optimized spectroscopy (TROSY) NMR study on a series of constructs in which only one of the protomer types is NMR-labeled. Our results show positive cooperativity of NTD up/down equilibria between neighboring protomers, allowing us to define interprotomer pathways that mediate the allosteric communication between subunits. Notably, the perturbed up/down NTD equilibrium in mutant subunits is partially restored by neighboring WT protomers, as is the two-pronged binding of the UBXD1 adaptor that is affected in disease. This work highlights the plasticity of p97 and how subtle perturbations to its free-energy landscape lead to significant changes in NTD conformation and adaptor binding.
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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.