期刊
MOLECULAR CELL
卷 81, 期 17, 页码 3496-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2021.07.023
关键词
-
资金
- Alzheimer's Association research fellowship
- NIH [AG002132, AG068125]
The Hsp90 chaperone facilitates the folding and activation of hundreds of client proteins in the cell, with FKBP51 serving as a catalytic co-chaperone during the folding process. The cryo-EM structure of the human Hsp90:FKBP51:p23 complex revealed the key interactions between cochaperones and Hsp90 during client maturation.
The Hsp90 chaperone promotes folding and activation of hundreds of client proteins in the cell through an ATP-dependent conformational cycle guided by distinct cochaperone regulators. The FKBP51 immunophilin binds Hsp90 with its tetratricopeptide repeat (TPR) domain and catalyzes peptidyl-prolyl isomerase (PPIase) activity during folding of kinases, nuclear receptors, and tau. Here we determined the cryoelectron microscopy (cryo-EM) structure of the human Hsp90:FKBP51:p23 complex to 3.3 A, which, together with mutagenesis and crosslinking analyses, reveals the basis for cochaperone binding to Hsp90 during client maturation. A helix extension in the TPR functions as a key recognition element, interacting across the Hsp90 C-terminal dimer interface presented in the closed, ATP conformation. The PPIase domain is positioned along the middle domain, adjacent to Hsp90 client binding sites, whereas a single p23 makes stabilizing interactions with the N-terminal dimer. With this architecture, FKBP51 is positioned to act on specific client residues presented during Hsp90-catalyzed remodeling.
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