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Dynamic tyrosine phosphorylation modulates cycling of the HSP90-P50(CDC37)-AHA1 chaperone machine
journal contribution
posted on 2023-06-08, 14:13 authored by Wanping Xu, Mehdi Mollapour, Chrisostomos ProdromouChrisostomos Prodromou, Suiquan Wang, Bradley T Scroggins, Zach Palchick, Kristin Beebe, Marco Siderius, Min-Jung Lee, Anthony Couvillon, Jane B Trepel, Yoshihiko Miyata, Robert Matts, Len NeckersMany critical protein kinases rely on the Hsp90 chaperone machinery for stability and function. After initially forming a ternary complex with kinase client and the cochaperone p50(Cdc37), Hsp90 proceeds through a cycle of conformational changes facilitated by ATP binding and hydrolysis. Progression through the chaperone cycle requires release of p50(Cdc37) and recruitment of the ATPase activating cochaperone AHA1, but the molecular regulation of this complex process at the cellular level is poorly understood. We demonstrate that a series of tyrosine phosphorylation events, involving both p50(Cdc37) and Hsp90, are minimally sufficient to provide directionality to the chaperone cycle. p50(Cdc37) phosphorylation on Y4 and Y298 disrupts client-p50(Cdc37) association, while Hsp90 phosphorylation on Y197 dissociates p50(Cdc37) from Hsp90. Hsp90 phosphorylation on Y313 promotes recruitment of AHA1, which stimulates Hsp90 ATPase activity, furthering the chaperoning process. Finally, at completion of the chaperone cycle, Hsp90 Y627 phosphorylation induces dissociation of the client and remaining cochaperones.
History
Publication status
- Published
Journal
Molecular CellISSN
1097-2765Publisher
ElsevierExternal DOI
Issue
3Volume
47Page range
434-443Department affiliated with
- Biochemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2013-01-15Usage metrics
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