Dynamic tyrosine phosphorylation modulates cycling of the HSP90-P50(CDC37)-AHA1 chaperone machine

Xu, Wanping, Mollapour, Mehdi, Prodromou, Chrisostomos, Wang, Suiquan, Scroggins, Bradley T, Palchick, Zach, Beebe, Kristin, Siderius, Marco, Lee, Min-Jung, Couvillon, Anthony, Trepel, Jane B, Miyata, Yoshihiko, Matts, Robert and Neckers, Len (2012) Dynamic tyrosine phosphorylation modulates cycling of the HSP90-P50(CDC37)-AHA1 chaperone machine. Molecular Cell, 47 (3). pp. 434-443. ISSN 1097-2765

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Abstract

Many 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.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science
Depositing User: Deeptima Massey
Date Deposited: 15 Jan 2013 15:49
Last Modified: 15 Jan 2013 15:49
URI: http://sro.sussex.ac.uk/id/eprint/43465
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