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    Two-step activation mechanism of the ClpB Disaggregase for sequential substrate threading by the Main ATPase Motor

    Deville, C. and Franke, K. and Mogk, A. and Bukau, B. and Saibil, Helen R. (2019) Two-step activation mechanism of the ClpB Disaggregase for sequential substrate threading by the Main ATPase Motor. Cell Reports 27 (12), 3433-3446.e4. ISSN 2211-1247.

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    Abstract

    AAA+ proteins form asymmetric hexameric rings that hydrolyze ATP and thread substrate proteins through a central channel via mobile substrate-binding pore loops. Understanding how ATPase and threading activities are regulated and intertwined is key to understanding the AAA+ protein mechanism. We studied the disaggregase ClpB, which contains tandem ATPase domains (AAA1, AAA2) and shifts between low and high ATPase and threading activities. Coiled-coil M-domains repress ClpB activity by encircling the AAA1 ring. Here, we determine the mechanism of ClpB activation by comparing ATPase mechanisms and cryo-EM structures of ClpB wild-type and a constitutively active ClpB M-domain mutant. We show that ClpB activation reduces ATPase cooperativity and induces a sequential mode of ATP hydrolysis in the AAA2 ring, the main ATPase motor. AAA1 and AAA2 rings do not work synchronously but in alternating cycles. This ensures high grip, enabling substrate threading via a processive, rope-climbing mechanism.

    Metadata

    Item Type: Article
    Keyword(s) / Subject(s): protein disaggregation, protein unfolding, AAA+, Hsp100, chaperone, cryo-EM
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Depositing User: Administrator
    Date Deposited: 24 Jun 2019 13:37
    Last Modified: 02 Aug 2023 17:52
    URI: https://eprints.bbk.ac.uk/id/eprint/27915

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