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Valosin-containing protein (VCP)–Adaptor Interactions are Exceptionally Dynamic and Subject to Differential Modulation by a VCP Inhibitor

Xue, Liang and Blythe, Emily E. and Freiberger, Elyse C. and Mamrosh, Jennifer and Hebert, Alexander S. and Reitsma, Justin M. and Hess, Sonja and Coon, Joshua J. and Deshaies, Raymond (2016) Valosin-containing protein (VCP)–Adaptor Interactions are Exceptionally Dynamic and Subject to Differential Modulation by a VCP Inhibitor. Molecular and Cellular Proteomics, 15 (9). pp. 2970-2986. ISSN 1535-9476. PMCID PMC5013311. https://resolver.caltech.edu/CaltechAUTHORS:20160718-111759001

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Abstract

Protein quality control (PQC) plays an important role in stemming neurodegenerative diseases and is essential for the growth of some cancers. Valosin-containing protein (VCP)/p97 plays a pivotal role in multiple PQC pathways by interacting with numerous adaptors that link VCP to specific PQC pathways and substrates and influence the post-translational modification state of substrates. However, our poor understanding of the specificity and architecture of the adaptors, and the dynamic properties of their interactions with VCP hinders our understanding of fundamental features of PQC and how modulation of VCP activity can best be exploited therapeutically. In this study we use multiple mass spectrometry-based proteomic approaches combined with biophysical studies to characterize the interaction of adaptors with VCP. Our results reveal that most VCP-adaptor interactions are characterized by rapid dynamics that in some cases are modulated by the VCP inhibitor NMS873. These findings have significant implications for both the regulation of VCP function and the impact of VCP inhibition on different VCP-adaptor complexes.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1074/mcp.M116.061036DOIArticle
http://www.mcponline.org/content/15/9/2970PublisherArticle
http://www.mcponline.org/content/15/9/2970/suppl/DC1PublisherSupplemental Data
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013311/PubMed CentralArticle
ORCID:
AuthorORCID
Blythe, Emily E.0000-0001-6363-2644
Hess, Sonja0000-0002-5904-9816
Deshaies, Raymond0000-0002-3671-9354
Alternate Title:VCP-adaptor interactions are exceptionally dynamic and subject to differential modulation by a VCP inhibitor
Additional Information:© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Received May 13, 2016; Revision received July 8, 2016; Accepted July 12, 2016; First Published on July 12, 2016. This work was supported by the Gordon and Betty Moore Foundation, through Grant GBMF775, the Beckman Institute and the NIH through Grant 1S10RR029594 (to SH). J.M.R. was supported by a postdoctoral fellowship from NIH (F32 GM112308-03). R.J.D. is an Investigator of the Howard Hughes Medical Institute and this work was funded by HHMI. E.E.B. is supported by an NIH Training Grant (T32 GM007616). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Author contributions: L.X. and R.J.D. designed research; L.X., E.E.B., E.C.F., and A.S.H. performed research; J.M.R. contributed new reagents or analytic tools; L.X., E.E.B., E.C.F., and J.M. analyzed data; L.X., E.E.B., J.M., and R.J.D. wrote the paper; S.H., J.J.C., and R.J.D. supervised research. Additional Information: Supplemental data set containing 7 Figs. and 11 Tables. The mass spectrometry proteomics data for supplemental Table S1, S2, and S5 have been deposited to the Chorus Project (chorusproject.org) with the project identifier 1068. Other mass spectrometry proteomics data have been deposited to ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository (68) with the data set identifier PXD004105.
Funders:
Funding AgencyGrant Number
Gordon and Betty Moore FoundationGBMF775
Caltech Beckman InstituteUNSPECIFIED
NIH1S10RR029594-01A1
NIH Postdoctoral FellowshipF32 GM112308-03
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NIH Predoctoral FellowshipT32 GM007616
Issue or Number:9
PubMed Central ID:PMC5013311
Record Number:CaltechAUTHORS:20160718-111759001
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160718-111759001
Official Citation:Liang Xue, Emily E. Blythe, Elyse C. Freiberger, Jennifer L. Mamrosh, Alexander S. Hebert, Justin M. Reitsma, Sonja Hess, Joshua J. Coon, and Raymond J. Deshaies Valosin-containing protein (VCP)–Adaptor Interactions are Exceptionally Dynamic and Subject to Differential Modulation by a VCP Inhibitor Mol Cell Proteomics 2016 15: 2970-2986. First Published on July 12, 2016, doi:10.1074/mcp.M116.061036
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:69094
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:27 Jul 2016 16:12
Last Modified:03 Oct 2019 10:19

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