Structure of Hsp90–p23–GR reveals the Hsp90 client-remodelling mechanism

Chari M. Noddings, Ray Yu-Ruei Wang, Jill L. Johnson and David A. Agard ()
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Chari M. Noddings: University of California, San Francisco
Ray Yu-Ruei Wang: University of California, San Francisco
Jill L. Johnson: University of Idaho
David A. Agard: University of California, San Francisco

Nature, 2022, vol. 601, issue 7893, 465-469

Abstract: Abstract Hsp90 is a conserved and essential molecular chaperone responsible for the folding and activation of hundreds of ‘client’ proteins1–3. The glucocorticoid receptor (GR) is a model client that constantly depends on Hsp90 for activity4–9. GR ligand binding was previously shown to be inhibited by Hsp70 and restored by Hsp90, aided by the co-chaperone p2310. However, a molecular understanding of the chaperone-mediated remodelling that occurs between the inactive Hsp70–Hsp90 ‘client-loading complex’ and an activated Hsp90–p23 ‘client-maturation complex’ is lacking for any client, including GR. Here we present a cryo-electron microscopy (cryo-EM) structure of the human GR-maturation complex (GR–Hsp90–p23), revealing that the GR ligand-binding domain is restored to a folded, ligand-bound conformation, while being simultaneously threaded through the Hsp90 lumen. In addition, p23 directly stabilizes native GR using a C-terminal helix, resulting in enhanced ligand binding. This structure of a client bound to Hsp90 in a native conformation contrasts sharply with the unfolded kinase–Hsp90 structure11. Thus, aided by direct co-chaperone–client interactions, Hsp90 can directly dictate client-specific folding outcomes. Together with the GR-loading complex structure12, we present the molecular mechanism of chaperone-mediated GR remodelling, establishing the first, to our knowledge, complete chaperone cycle for any Hsp90 client.

Date: 2022
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DOI: 10.1038/s41586-021-04236-1

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