Proteostasis involves degradation and recycling of proteins from organelles, membranes, and multiprotein complexes. These processes can depend on protein extraction and unfolding by the essential mechanoenzyme valosin-containing protein (VCP) and on ubiquitin chain remodeling by ubiquitin-specific proteases known as deubiquitinases (DUBs). How the activities of VCP and DUBs are coordinated is poorly understood. Here, we focus on the DUB VCPIP1, a VCP interactor required for post-mitotic Golgi and ER organization. We determine ∼3.3 Å cryogenic electron microscopy structures of VCP-VCPIP1 complexes in the absence of added nucleotide or the presence of an ATP analog. We find that up to 3 VCPIP1 protomers interact with the VCP hexamer to position VCPIP1’s catalytic domain at the exit of VCP’s central pore, poised to cleave ubiquitin following substrate unfolding. We observe competition between VCPIP1 and other cofactors for VCP binding and show that VCP stimulates VCPIP1’s DUB activity. Together, our data suggest how the two enzyme activities can be coordinated to regulate proteostasis.
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March 14 2025
Structural insights into the coupling between VCP, an essential unfoldase, and a deubiquitinase
Lauren E. Vostal
,
Lauren E. Vostal
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Laboratory of Chemistry and Cell Biology,
The Rockefeller University
, New York, NY, USA
2
Tri-Institutional PhD Program in Chemical Biology
, New York, NY, USA
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Noa E. Dahan
,
Noa E. Dahan
(Conceptualization, Formal analysis, Investigation, Methodology, Resources, Writing - review & editing)
1Laboratory of Chemistry and Cell Biology,
The Rockefeller University
, New York, NY, USA
3
The David Rockefeller Graduate Program in Bioscience, The Rockefeller University
, New York, NY, USA
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Matthew J. Reynolds
,
Matthew J. Reynolds
(Investigation)
4Laboratory of Structural Biophysics and Mechanobiology,
The Rockefeller University
, New York, NY, USA
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Lily I. Kronenberg
,
Lily I. Kronenberg
(Investigation, Writing - review & editing)
1Laboratory of Chemistry and Cell Biology,
The Rockefeller University
, New York, NY, USA
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Tarun M. Kapoor
(Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Validation, Writing - original draft, Writing - review & editing)
1Laboratory of Chemistry and Cell Biology,
The Rockefeller University
, New York, NY, USA
Correspondence to Tarun M. Kapoor: [email protected]
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Lauren E. Vostal
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing - original draft, Writing - review & editing
1Laboratory of Chemistry and Cell Biology,
The Rockefeller University
, New York, NY, USA
2
Tri-Institutional PhD Program in Chemical Biology
, New York, NY, USA
Noa E. Dahan
Conceptualization, Formal analysis, Investigation, Methodology, Resources, Writing - review & editing
1Laboratory of Chemistry and Cell Biology,
The Rockefeller University
, New York, NY, USA
3
The David Rockefeller Graduate Program in Bioscience, The Rockefeller University
, New York, NY, USA
Matthew J. Reynolds
Investigation
4Laboratory of Structural Biophysics and Mechanobiology,
The Rockefeller University
, New York, NY, USA
Lily I. Kronenberg
Investigation, Writing - review & editing
1Laboratory of Chemistry and Cell Biology,
The Rockefeller University
, New York, NY, USA
Correspondence to Tarun M. Kapoor: [email protected]
Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. T.M. Kapoor reported other from RADD Pharma outside the submitted work. No other disclosures were reported.
Received:
October 24 2024
Revision Received:
January 08 2025
Accepted:
February 09 2025
Online ISSN: 1540-8140
Print ISSN: 0021-9525
Funding
Funder(s):
National Institutes of Health
- Award Id(s): GM1300234,GM115327,GM136640,TGM144299
© 2025 Vostal et al.
2025
Vostal et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Cell Biol (2025) 224 (5): e202410148.
Article history
Received:
October 24 2024
Revision Received:
January 08 2025
Accepted:
February 09 2025
Citation
Lauren E. Vostal, Noa E. Dahan, Matthew J. Reynolds, Lily I. Kronenberg, Tarun M. Kapoor; Structural insights into the coupling between VCP, an essential unfoldase, and a deubiquitinase. J Cell Biol 5 May 2025; 224 (5): e202410148. doi: https://doi.org/10.1083/jcb.202410148
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