title: Valosin-containing protein (VCP)-Adaptor Interactions are Exceptionally Dynamic and Subject to Differential Modulation by a VCP Inhibitor.
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.
authors.affiliation: From the ‡Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, California 91125;
authors.forename: Liang
authors.identifier: 0000-0003-3606-4615
authors.initials: L
authors.lastname: Xue
authors.affiliation: From the ‡Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, California 91125;
authors.forename: Emily E
authors.initials: EE
authors.lastname: Blythe
authors.affiliation: §Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706;
authors.forename: Elyse C
authors.initials: EC
authors.lastname: Freiberger
authors.affiliation: From the ‡Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, California 91125;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Mamrosh
authors.affiliation: ¶Genome Center of Wisconsin, 425 Henry Mall, Madison, Wisconsin 53706;
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Hebert
authors.affiliation: From the ‡Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, California 91125;
authors.forename: Justin M
authors.initials: JM
authors.lastname: Reitsma
authors.affiliation: **Proteome Exploration Laboratory (PEL), Beckman Institute, Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125;
authors.forename: Sonja
authors.initials: S
authors.lastname: Hess
authors.affiliation: §Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706; ¶Genome Center of Wisconsin, 425 Henry Mall, Madison, Wisconsin 53706; ‖Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706;
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Coon
authors.affiliation: From the ‡Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, California 91125; ‡‡Howard Hughes Medical Institute, Pasadena, California 91125 deshaies@caltech.edu.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Deshaies
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002850:Chromatography, Gel; D005347:Fibroblasts / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D013058:Mass Spectrometry; D011485:Protein Binding; D060066:Protein Interaction Maps; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D013379:Substrate Specificity; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D020543:Proteome; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein