s41467-019-10463-y.pdf (3.22 MB)
Hsp90 middle domain phosphorylation initiates a complex conformational program to recruit the ATPase-stimulating cochaperone Aha1
journal contribution
posted on 2023-06-09, 17:51 authored by Wanping xu, Kristin Beebe, Juan D Chavez, Marta Boysen, YinYing Lu, Abbey D Zuehlke, Dimitra Keramisanou, Jane B Trepel, Chrisostomos ProdromouChrisostomos Prodromou, Matthias P Mayer, James E Bruce, Ioannis Gelis, Len NeckersComplex 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 Hsp90a) 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.
Funding
Wellcome Trust; 095605/Z11/Z
History
Publication status
- Published
File Version
- Published version
Journal
Nature CommunicationsISSN
2041-1723Publisher
Nature ResearchExternal DOI
Volume
10Page range
2574-2587Department affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2019-06-17First Open Access (FOA) Date
2019-06-17First Compliant Deposit (FCD) Date
2019-06-15Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC