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

Publication date: Available online 7 April 2016
Source:Cell Reports
Author(s): Parul Mishra, Julia M. Flynn, Tyler N. Starr, Daniel N.A. Bolon
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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Teaser

Mishra et al. now examine the mechanism by which Hsp90 helps clients to mature by analyzing the effects of all individual mutations in the ATPase domain on yeast growth rate. The results indicate that both general and client-specific features of this domain contribute to chaperone function.


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