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bioRxiv · 10.1101/2021.01.21.427690

Structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client-maturation state

Lee, K.·Thwin, A. C.·Tse, E.·Gates, S. N.·Southworth, D. R.
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Abstract

The Hsp90 chaperone promotes the 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 the folding of kinases, nuclear receptors and tau. Here we have determined the cryo-EM structure of the human Hsp90:FKBP51:p23 complex to 3.3 [A] that, together with mutagenesis and crosslinking analysis, 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 Hsp90 client binding sites, while a single p23 makes stabilizing interactions with the N-terminal dimer. With this architecture, FKBP51 could thereby act on specific client residues presented during Hsp90-catalyzed remodeling.

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Lee, K., Thwin, A. C., Tse, E., Gates, S. N., Southworth, D. R.. 2021-01-22. Structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client-maturation state. https://doi.org/10.1101/2021.01.21.427690

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