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Cell Rep. 2016 Apr 19;15(3):588-598. doi: 10.1016/j.celrep.2016.03.046. Epub 2016 Apr 7.

Systematic Mutant Analyses Elucidate General and Client-Specific Aspects of Hsp90 Function.

Author information

1
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
2
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
3
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: dan.bolon@umassmed.edu.

Abstract

To probe the mechanism of the Hsp90 chaperone that is required for the maturation of many signaling proteins in eukaryotes, we analyzed the effects of all individual amino acid changes in the ATPase domain on yeast growth rate. The sensitivity of a position to mutation was strongly influenced by proximity to the phosphates of ATP, indicating that ATPase-driven conformational changes impose stringent physical constraints on Hsp90. To investigate how these constraints may vary for different clients, we performed biochemical analyses on a panel of Hsp90 mutants spanning the full range of observed fitness effects. We observed distinct effects of nine Hsp90 mutations on activation of v-src and glucocorticoid receptor (GR), indicating that different chaperone mechanisms can be utilized for these clients. These results provide a detailed guide for understanding Hsp90 mechanism and highlight the potential for inhibitors of Hsp90 that target a subset of clients.

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PMID:
27068472
PMCID:
PMC4838542
DOI:
10.1016/j.celrep.2016.03.046
[Indexed for MEDLINE]
Free PMC Article

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