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

Citation:

Edward C. Twomey, Zhejian Ji, Thomas E. Wales, Nicholas O. Bodnar, Scott B. Ficarro, Jarrod A. Marto, John R. Engen, and Tom A. Rapoport. 2019. “Substrate processing by the Cdc48 ATPase complex is initiated by ubiquitin unfolding.” Science.

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.