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

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.

SUBMITTER: Twomey EC

PROVIDER: S-EPMC6980381 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Twomey Edward C EC Ji Zhejian Z Wales Thomas E TE Bodnar Nicholas O NO Ficarro Scott B SB Marto Jarrod A JA Engen John R JR Rapoport Tom A TA

Science (New York, N.Y.) 20190627 6452

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 initiat ...[more]

PMID: 31249135

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