Hsp90 middle domain phosphorylation initiates a complex conformational program to recruit the ATPase-stimulating cochaperone Aha1

Wanping Xu, Kristin Beebe, Juan D. Chavez, Marta Boysen, YinYing Lu, Abbey D. Zuehlke, Dimitra Keramisanou, Jane B. Trepel, Christosomos Prodromou, Matthias P. Mayer, James E. Bruce, Ioannis Gelis and Len Neckers ()
Additional contact information
Wanping Xu: National Cancer Institute
Kristin Beebe: National Cancer Institute
Juan D. Chavez: University of Washington School of Medicine
Marta Boysen: University of Heidelberg
YinYing Lu: National Cancer Institute
Abbey D. Zuehlke: National Cancer Institute
Dimitra Keramisanou: University of South Florida
Jane B. Trepel: National Cancer Institute
Christosomos Prodromou: University of Sussex
Matthias P. Mayer: University of Heidelberg
James E. Bruce: University of Washington School of Medicine
Ioannis Gelis: University of South Florida
Len Neckers: National Cancer Institute

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Complex conformational dynamics are essential for function of the dimeric molecular chaperone heat shock protein 90 (Hsp90), including transient, ATP-biased N-domain dimerization that is necessary to attain ATPase competence. The intrinsic, but weak, ATP hydrolyzing activity of human Hsp90 is markedly enhanced by the co-chaperone Aha1. However, the cellular concentration of Aha1 is substoichiometric relative to Hsp90. Here we report that initial recruitment of this cochaperone to Hsp90 is markedly enhanced by phosphorylation of a highly conserved tyrosine (Y313 in Hsp90α) in the Hsp90 middle domain. Importantly, phosphomimetic mutation of Y313 promotes formation of a transient complex in which both N- and C-domains of Aha1 bind to distinct surfaces of the middle domains of opposing Hsp90 protomers prior to ATP-directed N-domain dimerization. Thus, Y313 represents a phosphorylation-sensitive conformational switch, engaged early after client loading, that affects both local and long-range conformational dynamics to facilitate initial recruitment of Aha1 to Hsp90.

Date: 2019
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DOI: 10.1038/s41467-019-10463-y

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