Structure of the Cdc48 segregase in the act of unfolding an authentic substrate

By Ian Cooney¹, Han Han¹, Michael G. Stewart¹, Richard H. Carson², Daniel T. Hanson¹, Janet H. Iwasa¹, John C. Price², Christopher P. Hill¹, Peter S. Shen¹

¹Department of Biochemistry, University of Utah, ²Department of Chemistry and Biochemistry, Brigham Young University

The cellular machine Cdc48 functions in multiple biological pathways by segregating its protein substrates from a variety of stable environments such as organelles or multi-subunit complexes. Despite extensive studies, the mechanism of Cdc48 has remained obscure, and its reported structures are inconsistent with models of substrate translocation proposed for other AAA+ ATPases (adenosine triphosphatases). Here, we report a 3.7-angstrom–resolution structure of Cdc48 in complex with an adaptor protein and a native substrate. Cdc48 engages substrate by adopting a helical configuration of substrate-binding residues that extends through the central pore of both of the ATPase rings. These findings indicate a unified hand-over-hand mechanism of protein translocation by Cdc48 and other AAA+ ATPases.

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