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

xu, Wanping, Beebe, Kristin, Chavez, Juan D, Boysen, Marta, Lu, YinYing, Zuehlke, Abbey D, Keramisanou, Dimitra, Trepel, Jane B, Prodromou, Chrisostomos, Mayer, Matthias P, Bruce, James E, Gelis, Ioannis and Neckers, Len (2019) Hsp90 middle domain phosphorylation initiates a complex conformational program to recruit the ATPase-stimulating cochaperone Aha1. Nature Communications, 10. pp. 2574-2587. ISSN 2041-1723

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Abstract

Complex conformational dynamics are essential for function of the dimeric molecular cha- perone heat shock protein 90 (Hsp90), including transient, ATP-biased N-domain dimer- ization 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.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science > QH Natural history > QH0301 Biology
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Depositing User: Chrisostomos Prodromou
Date Deposited: 17 Jun 2019 14:16
Last Modified: 01 Jul 2019 12:30
URI: http://sro.sussex.ac.uk/id/eprint/83835

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Project NameSussex Project NumberFunderFunder Ref
UnsetUnsetWellcome Trust095605/Z11/Z