1. Translocation of polyubiquitinated protein substrates by the hexameric Cdc48 ATPase.
- Author
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Ji Z, Li H, Peterle D, Paulo JA, Ficarro SB, Wales TE, Marto JA, Gygi SP, Engen JR, and Rapoport TA
- Subjects
- Nucleocytoplasmic Transport Proteins genetics, Nucleocytoplasmic Transport Proteins metabolism, Proteasome Endopeptidase Complex metabolism, Protein Binding, Protein Transport, Protein Unfolding, Proteolysis, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae Proteins genetics, Ubiquitinated Proteins genetics, Ubiquitination, Valosin Containing Protein genetics, Vesicular Transport Proteins genetics, Vesicular Transport Proteins metabolism, Polyubiquitin metabolism, Saccharomyces cerevisiae enzymology, Saccharomyces cerevisiae Proteins metabolism, Ubiquitinated Proteins metabolism, Valosin Containing Protein metabolism
- Abstract
The hexameric Cdc48 ATPase (p97 or VCP in mammals) cooperates with its cofactor Ufd1/Npl4 to extract polyubiquitinated proteins from membranes or macromolecular complexes for degradation by the proteasome. Here, we clarify how the Cdc48 complex unfolds its substrates and translocates polypeptides with branchpoints. The Cdc48 complex recognizes primarily polyubiquitin chains rather than the attached substrate. Cdc48 and Ufd1/Npl4 cooperatively bind the polyubiquitin chain, resulting in the unfolding of one ubiquitin molecule (initiator). Next, the ATPase pulls on the initiator ubiquitin and moves all ubiquitin molecules linked to its C terminus through the central pore of the hexameric double ring, causing transient ubiquitin unfolding. When the ATPase reaches the isopeptide bond of the substrate, it can translocate and unfold both N- and C-terminal segments. Ubiquitins linked to the branchpoint of the initiator dissociate from Ufd1/Npl4 and move outside the central pore, resulting in the release of unfolded, polyubiquitinated substrate from Cdc48., Competing Interests: Declaration of interests J.A.M. serves on the scientific advisory board of 908 Devices and receives sponsored research support from AstraZeneca and Vertex. All other authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2022
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