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Science. 2019 Jun 27. pii: eaax1033. doi: 10.1126/science.aax1033. [Epub ahead of print]

Substrate processing by the Cdc48 ATPase complex is initiated by ubiquitin unfolding.

Author information

1
Department of Cell Biology, Harvard Medical School, and Howard Hughes Medical Institute, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
2
Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA.
3
Department of Cancer Biology, Department of Oncologic Pathology, and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
4
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
5
Department of Cell Biology, Harvard Medical School, and Howard Hughes Medical Institute, 240 Longwood Avenue, Boston, Massachusetts 02115, USA. tom_rapoport@hms.harvard.edu.
#
Contributed equally

Abstract

The Cdc48 ATPase (p97 or VCP in mammals) and its cofactor Ufd1/Npl4 extract poly-ubiquitinated proteins from membranes or macromolecular complexes for subsequent degradation by the proteasome. How Cdc48 processes its diverse and often well-folded substrates is unclear. Here, we report cryo-EM structures of the Cdc48 ATPase in complex with Ufd1/Npl4 and poly-ubiquitinated substrate. The structures show that the Cdc48 complex initiates substrate processing by unfolding a ubiquitin molecule. The unfolded ubiquitin molecule binds to Npl4 and projects its N-terminal segment through both hexameric ATPase rings. Pore loops of the second ring form a staircase that acts as a conveyer belt to move the polypeptide through the central pore. Inducing the unfolding of ubiquitin allows the Cdc48 ATPase complex to process a broad range of substrates.

PMID:
31249135
DOI:
10.1126/science.aax1033

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