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Conformational Plasticity of the ClpAP AAA+ Protease Couples Protein Unfolding and Proteolysis

By Kyle E Lopez, Alexandrea N. Rizo, Eric Tse, JiaBei Lin, Nathaniel W Scull, Aye C Thwin, Aaron L Lucius, James Shorter, Daniel R Southworth

Posted 28 Oct 2019
bioRxiv DOI: 10.1101/820209 (published DOI: 10.1038/s41594-020-0409-5)

The ClpAP complex functions as a “bacterial proteasome” that simultaneously unfolds and degrades proteins targeted for destruction. ClpA utilizes two AAA+ domains per protomer to power substrate unfolding and translocation into the ClpP proteolytic chamber. To understand this mechanism, we determined high-resolution structures of wildtype E. coli ClpAP in distinct substrate-bound states. ClpA forms a spiral with substrate contacts across both AAA+ domains, while protomers at the seam undergo nucleotide-specific rearrangements indicating a conserved rotary mechanism. ClpA IGL loops extend flexibly to bind the planar, heptameric ClpP surface and support a large ClpA-P rotation that re-orients the translocation channel. The symmetry mismatch is maintained at the spiral seam through bind and release states of the IGL loops, which appear precisely coupled to substrate translocation. Thus, ClpA rotates around the apical surface of ClpP to processively translocate substrate into the protease.

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