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Multisystem Proteinopathy Mutations in VCP/p97 Increase NPLOC4·UFD1L Binding and Substrate Processing

Blythe, Emily E. and Gates, Stephanie N. and Deshaies, Raymond J. and Martin, Andreas (2019) Multisystem Proteinopathy Mutations in VCP/p97 Increase NPLOC4·UFD1L Binding and Substrate Processing. Structure, 27 (12). pp. 1820-1829. ISSN 0969-2126. PMCID PMC6929323.

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Valosin-containing protein (VCP)/p97 is an essential ATP-dependent protein unfoldase. Dominant mutations in p97 cause multisystem proteinopathy (MSP), a disease affecting the brain, muscle, and bone. Despite the identification of numerous pathways that are perturbed in MSP, the molecular-level defects of these p97 mutants are not completely understood. Here, we use biochemistry and cryoelectron microscopy to explore the effects of MSP mutations on the unfoldase activity of p97 in complex with its substrate adaptor NPLOC4⋅UFD1L (UN). We show that all seven analyzed MSP mutants unfold substrates faster. Mutant homo- and heterohexamers exhibit tighter UN binding and faster substrate processing. Our structural studies suggest that the increased UN affinity originates from a decoupling of p97's nucleotide state and the positioning of its N-terminal domains. Together, our data support a gain-of-function model for p97-UN-dependent processes in MSP and underscore the importance of N-terminal domain movements for adaptor recruitment and substrate processing by p97.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Blythe, Emily E.0000-0001-6363-2644
Gates, Stephanie N.0000-0002-4312-2900
Deshaies, Raymond J.0000-0002-3671-9354
Martin, Andreas0000-0003-0923-3284
Additional Information:© 2019 Elsevier Ltd. Received 3 July 2019, Revised 19 August 2019, Accepted 20 September 2019, Available online 14 October 2019. We thank Rebecca Voorhees for advice on mammalian protein purification; Xiawei Huang for help with cloning; and the Deshaies and Martin labs for helpful discussion. A.M. is an HHMI investigator, R.J.D. was an HHMI investigator, and this work was funded by HHMI, the NIH (R01-GM094497 to A.M.), and a gift from Amgen to Caltech. S.N.G. is a Howard Hughes Medical Institute Fellow of the Damon Runyon Cancer Research Foundation, DRG-2342-18. Author Contributions: Conceptualization, E.E.B., S.N.G., R.J.D., and A.M.; Methodology, E.E.B., S.N.G., R.J.D., and A.M; Investigation, E.E.B. and S.N.G.; Writing – Original Draft, E.E.B., S.N.G., and A.M.; Writing – Review & Editing, E.E.B., S.N.G., R.J.D., and A.M; Supervision, R.J.D. and A.M.; Funding Acquisition, R.J.D. and A.M. E.E.B., S.N.G., and A.M. declare no competing interests. R.J.D. is currently Senior Vice President of Global Research at Amgen.
Funding AgencyGrant Number
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Damon Runyon Cancer Research FoundationDRG-2342-18
Subject Keywords:p97; VCP; Ufd1-Npl4; multisystem proteinopathy; ATP-dependent protein unfolding; AAA+ ATPase
Issue or Number:12
PubMed Central ID:PMC6929323
Record Number:CaltechAUTHORS:20191014-113833407
Persistent URL:
Official Citation:Emily E. Blythe, Stephanie N. Gates, Raymond J. Deshaies, Andreas Martin, Multisystem Proteinopathy Mutations in VCP/p97 Increase NPLOC4·UFD1L Binding and Substrate Processing, Structure, Volume 27, Issue 12, 2019, Pages 1820-1829.e4, ISSN 0969-2126, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:99252
Deposited By: Tony Diaz
Deposited On:14 Oct 2019 18:55
Last Modified:30 Jun 2020 22:25

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