Structural basis for substrate gripping and translocation by the ClpB AAA+ disaggregase

Alexandrea N. Rizo, JiaBei Lin, Stephanie N. Gates, Eric Tse, Stephen M. Bart, Laura M. Castellano, Frank DiMaio, James Shorter and Daniel R. Southworth ()
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Alexandrea N. Rizo: University of Michigan
JiaBei Lin: Perelman School of Medicine at the University of Pennsylvania
Stephanie N. Gates: University of Michigan
Eric Tse: University of California
Stephen M. Bart: Perelman School of Medicine at the University of Pennsylvania
Laura M. Castellano: Perelman School of Medicine at the University of Pennsylvania
Frank DiMaio: University of Washington
James Shorter: Perelman School of Medicine at the University of Pennsylvania
Daniel R. Southworth: University of California

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Bacterial ClpB and yeast Hsp104 are homologous Hsp100 protein disaggregases that serve critical functions in proteostasis by solubilizing protein aggregates. Two AAA+ nucleotide binding domains (NBDs) power polypeptide translocation through a central channel comprised of a hexameric spiral of protomers that contact substrate via conserved pore-loop interactions. Here we report cryo-EM structures of a hyperactive ClpB variant bound to the model substrate, casein in the presence of slowly hydrolysable ATPγS, which reveal the translocation mechanism. Distinct substrate-gripping interactions are identified for NBD1 and NBD2 pore loops. A trimer of N-terminal domains define a channel entrance that binds the polypeptide substrate adjacent to the topmost NBD1 contact. NBD conformations at the seam interface reveal how ATP hydrolysis-driven substrate disengagement and re-binding are precisely tuned to drive a directional, stepwise translocation cycle.

Date: 2019
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DOI: 10.1038/s41467-019-10150-y

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