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

By Alexandrea N. Rizo, JiaBei Lin, Stephanie N. Gates, Eric Tse, Stephen M Bart, Laura M Castellano, Frank Dimaio, James Shorter, Daniel R Southworth

Posted 26 Sep 2018
bioRxiv DOI: 10.1101/428458 (published DOI: 10.1038/s41467-019-10150-y)

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. To elucidate the translocation mechanism, we determined the cryo-EM structure of a hyperactive ClpB variant to 2.9 angstrom resolution bound to the model substrate, casein in the presence of slowly hydrolysable ATPĪ³S. Distinct substrate-gripping mechanisms are identified for NBD1 and NBD2 pore loops. A trimer of N-terminal domains define a channel entrance that binds the polypeptide substrate adjacent the topmost NBD1 contact. NBD conformations at the spiral seam reveal how ATP hydrolysis and substrate engagement or disengagement are precisely tuned to drive a stepwise translocation cycle.

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