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

Edward C. Twomey, Zhejian Ji, Thomas E. Wales, Nicholas O. Bodnar, Scott B. Ficarro, Jarrod A. Marto, John R. Engen, Tom A. Rapoport

Research output: Contribution to journalArticlepeer-review

Abstract

The Cdc48 adenosine triphosphatase (ATPase) (p97 or valosin-containing protein in mammals) and its cofactor Ufd1/Npl4 extract polyubiquitinated 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–electron microscopy structures of the Cdc48 ATPase in complex with Ufd1/Npl4 and polyubiquitinated 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.

Original languageEnglish (US)
Article numbereaax1033
JournalScience
Volume365
Issue number6452
DOIs
StatePublished - Aug 2 2019
Externally publishedYes

ASJC Scopus subject areas

  • General

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