The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state.

Autor:	Lee K; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158, USA., Thwin AC; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158, USA., Nadel CM; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158, USA., Tse E; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158, USA., Gates SN; Graduate Program in Chemical Biology, University of Michigan, Ann Arbor, MI, USA., Gestwicki JE; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA., Southworth DR; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: daniel.southworth@ucsf.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2021 Sep 02; Vol. 81 (17), pp. 3496-3508.e5. Date of Electronic Publication: 2021 Aug 10.
DOI:	10.1016/j.molcel.2021.07.023
Abstrakt:	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 Å, 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. Competing Interests: Declaration of interests The authors declare no competing interests. (Published by Elsevier Inc.)
Databáze:	MEDLINE
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