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

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 pathway...

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Published inMolecular & cellular proteomics Vol. 15; no. 9; pp. 2970 - 2986
Main Authors Xue, Liang, Blythe, Emily E., Freiberger, Elyse C., Mamrosh, Jennifer L., Hebert, Alexander S., Reitsma, Justin M., Hess, Sonja, Coon, Joshua J., Deshaies, Raymond J.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 01.09.2016
The American Society for Biochemistry and Molecular Biology
Subjects
Adenosine Triphosphatases - metabolism
Cell Cycle Proteins - metabolism
Cells, Cultured
Chromatography, Gel
Fibroblasts - metabolism
HEK293 Cells
Humans
Mass Spectrometry
Protein Binding
Protein Interaction Maps
Proteome - metabolism
Proteomics - methods
Substrate Specificity
Valosin Containing Protein
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Summary: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.
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ISSN:1535-9476
1535-9484
DOI:10.1074/mcp.M116.061036