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-Structure paper
タイトル | Structure of Hsp90-p23-GR reveals the Hsp90 client-remodelling mechanism. |
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ジャーナル・号・ページ | Nature, Vol. 601, Issue 7893, Page 465-469, Year 2022 |
掲載日 | 2021年12月22日 |
著者 | Chari M Noddings / Ray Yu-Ruei Wang / Jill L Johnson / David A Agard / |
PubMed 要旨 | Hsp90 is a conserved and essential molecular chaperone responsible for the folding and activation of hundreds of 'client' proteins. The glucocorticoid receptor (GR) is a model client that constantly ...Hsp90 is a conserved and essential molecular chaperone responsible for the folding and activation of hundreds of 'client' proteins. The glucocorticoid receptor (GR) is a model client that constantly depends on Hsp90 for activity. GR ligand binding was previously shown to nr inhibited by Hsp70 and restored by Hsp90, aided by the co-chaperone p23. 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 structure. Thus, aided by direct co-chaperone-client interactions, Hsp90 can directly dictate client-specific folding outcomes. Together with the GR-loading complex structure, we present the molecular mechanism of chaperone-mediated GR remodelling, establishing the first, to our knowledge, complete chaperone cycle for any Hsp90 client. |
リンク | Nature / PubMed:34937936 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.56 - 3.63 Å |
構造データ | EMDB-23004, PDB-7krj: EMDB-23005: EMDB-23006: |
化合物 | ChemComp-ATP: ChemComp-MG: ChemComp-DEX: |
由来 |
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キーワード | CHAPERONE (シャペロン) / ligand binding (リガンド) / ATP binding (アデノシン三リン酸) / protein folding (フォールディング) / cryo-EM (低温電子顕微鏡法) |