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Cooperation of local motions in the Hsp90 molecular chaperone ATPase mechanism
journal contribution
posted on 2023-06-09, 06:06 authored by Andrea Schulze, Gerti Beliu, Dominic A Helmerich, Jonathan Schubert, Laurence PearlLaurence Pearl, Chrisostomos ProdromouChrisostomos Prodromou, Hannes NeuweilerThe Hsp90 chaperone is a central node of protein homeostasis activating a large number of diverse client proteins. Hsp90 functions as a molecular clamp that closes and opens in response to the binding and hydrolysis of ATP. Crystallographic studies define distinct conformational states of the mechanistic core implying structural changes that have not yet been observed in solution. Here, we engineered one-nanometer fluorescence probes based on photo-induced electron transfer into yeast Hsp90 to observe these motions. We found that the ATPase activity of the chaperone was reflected in the kinetics of specific structural rearrangements at remote positions that acted cooperatively. Nanosecond single-molecule fluorescence fluctuation analysis uncovered that critical structural elements that undergo rearrangement are mobile on a sub-millisecond time scale. We identified a two-step mechanism for lid closure over the nucleotide-binding pocket. The activating co-chaperone Aha1 mobilizes the lid of apo Hsp90, suggesting an early role in the catalytic cycle.
History
Publication status
- Published
File Version
- Accepted version
Journal
Nature Chemical BiologyISSN
1552-4450Publisher
Nature Publishing GroupExternal DOI
Issue
8Volume
12Page range
628-635Department affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2017-05-04First Open Access (FOA) Date
2017-05-04First Compliant Deposit (FCD) Date
2017-05-04Usage metrics
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