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 in: | Molecular & cellular proteomics Vol. 15; no. 9; p. 2970 |
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| Main Authors: | , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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United States
01.09.2016
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| ISSN: | 1535-9484, 1535-9484 |
| Online Access: | Get more information |
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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. |
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| AbstractList | 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. 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.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. |
| Author | Reitsma, Justin M Coon, Joshua J Hebert, Alexander S Xue, Liang Freiberger, Elyse C Hess, Sonja Deshaies, Raymond J Blythe, Emily E Mamrosh, Jennifer L |
| Author_xml | – sequence: 1 givenname: Liang orcidid: 0000-0003-3606-4615 surname: Xue fullname: Xue, Liang organization: From the ‡Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, California 91125 – sequence: 2 givenname: Emily E surname: Blythe fullname: Blythe, Emily E organization: From the ‡Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, California 91125 – sequence: 3 givenname: Elyse C surname: Freiberger fullname: Freiberger, Elyse C organization: §Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706 – sequence: 4 givenname: Jennifer L surname: Mamrosh fullname: Mamrosh, Jennifer L organization: From the ‡Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, California 91125 – sequence: 5 givenname: Alexander S surname: Hebert fullname: Hebert, Alexander S organization: ¶Genome Center of Wisconsin, 425 Henry Mall, Madison, Wisconsin 53706 – sequence: 6 givenname: Justin M surname: Reitsma fullname: Reitsma, Justin M organization: From the ‡Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, California 91125 – sequence: 7 givenname: Sonja surname: Hess fullname: Hess, Sonja organization: Proteome Exploration Laboratory (PEL), Beckman Institute, Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125 – sequence: 8 givenname: Joshua J surname: Coon fullname: Coon, Joshua J organization: §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 – sequence: 9 givenname: Raymond J surname: Deshaies fullname: Deshaies, Raymond J email: deshaies@caltech.edu organization: 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 |
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| SubjectTerms | 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 |
| Title | Valosin-containing protein (VCP)-Adaptor Interactions are Exceptionally Dynamic and Subject to Differential Modulation by a VCP Inhibitor |
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