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Structural pathway of regulated substrate transfer and threading through an Hsp100 disaggregase

Deville, C; Carroni, M; Franke, KB; Topf, M; Bukau, B; Mogk, A; Saibil, HR; (2017) Structural pathway of regulated substrate transfer and threading through an Hsp100 disaggregase. Science Advances , 3 (8) , Article e1701726. 10.1126/sciadv.1701726. Green open access

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Abstract

Refolding aggregated proteins is essential in combating cellular proteotoxic stress. Together with Hsp70, Hsp100 chaperones, including Escherichia coli ClpB, form a powerful disaggregation machine that threads aggregated polypeptides through the central pore of tandem adenosine triphosphatase (ATPase) rings. To visualize protein disaggregation, we determined cryo–electron microscopy structures of inactive and substrate-bound ClpB in the presence of adenosine 5′-O-(3-thiotriphosphate), revealing closed AAA+ rings with a pronounced seam. In the substrate-free state, a marked gradient of resolution, likely corresponding to mobility, spans across the AAA+ rings with a dynamic hotspot at the seam. On the seam side, the coiled-coil regulatory domains are locked in a horizontal, inactive orientation. On the opposite side, the regulatory domains are accessible for Hsp70 binding, substrate targeting, and activation. In the presence of the model substrate casein, the polypeptide threads through the entire pore channel and increased nucleotide occupancy correlates with higher ATPase activity. Substrate-induced domain displacements indicate a pathway of regulated substrate transfer from Hsp70 to the ClpB pore, inside which a spiral of loops contacts the substrate. The seam pore loops undergo marked displacements, along with ordering of the regulatory domains. These asymmetric movements suggest a mechanism for ATPase activation and substrate threading during disaggregation.

Type: Article
Title: Structural pathway of regulated substrate transfer and threading through an Hsp100 disaggregase
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/sciadv.1701726
Publisher version: https://doi.org/10.1126/sciadv.1701726
Language: English
Additional information: Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the advancement of Science. No claim to original U.S. government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY) https://creativecommons.org/licenses/by/4.0/
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: http://discovery.ucl.ac.uk/id/eprint/10073482
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