The Co-Chaperone Hch1 Regulates Hsp90 Function Differently than Its Homologue Aha1 and Confers Sensitivity to Yeast to the Hsp90 Inhibitor NVP-AUY922

Abstract

Hsp90 is a dimeric ATPase responsible for the activation or maturation of a specific set of substrate proteins termed ‘clients’. This molecular chaperone acts in the context of a structurally dynamic and highly regulated cycle involving ATP, co-chaperone proteins and clients. Co-chaperone proteins regulate conformational transitions that may be impaired in mutant forms of Hsp90. We report here that the in vivo impairment of commonly studied Hsp90 variants harbouring the G313S or A587T mutation are exacerbated by the co-chaperone Hch1p. Deletion of HCH1, but not AHA1, mitigates the temperature sensitive phenotype and high sensitivity to Hsp90 inhibitor drugs observed in Saccharomyces cerevisiae that express either of these two Hsp90 variants. Moreover, the deletion of HCH1 results in high resistance to Hsp90 inhibitors in yeast that express wildtype Hsp90. Conversely, the overexpression of Hch1p greatly increases sensitivity to Hsp90 inhibition in yeast expressing wildtype Hsp90. We conclude that despite the similarity between these two co-chaperones, Hch1p and Aha1p regulate Hsp90 function in distinct ways and likely independent of their roles as ATPase stimulators. We further conclude that Hch1p plays a critical role in regulating Hsp90 inhibitor drug sensitivity in yeast.

Interaction of Heat Shock Protein 90 and the Co-chaperone Cpr6 with Ura2, a Bifunctional Enzyme Required for Pyrimidine Biosynthesis

“…However, previous studies showed that cells that lack nonessential co-chaperones exhibit growth defects in cells expressing mutant Hsp90 (21,44). We compared the growth of a panel of Hsp90 temperature-sensitive mutants in WT (JJ816) or ⌬cpr6 (JJ110) cells that lacked chromosomal Hsp90 genes.…”

Exploring the Trypanosoma brucei Hsp83 Potential as a Target for Structure Guided Drug Design

“…First, due to the large structural rearrangements involved upon inhibitor association, the contribution from regions other than the nucleotide-binding pocket can be quite substantial and hard to predict by analyzing the structure alone. Second, the cellular effects of Hsp90 inhibitors are related to the conformational limitations imposed on the chaperone, affecting co-chaperone binding and long-range coupled motions observed between the NTD and CTD domains [64].…”

Expression of three topologically distinct membrane proteins elicits unique stress response pathways in the yeastSaccharomyces cerevisiae

“…We propose that this select group represents a set of misfolded membrane protein stress-responders and includes: 1) PRE2, which encodes the chymotrypsin-like subunit of the proteasome; 2) HSP30, which encodes a membrane-associated heat shock protein that regulates the yeast plasma membrane H ϩ -ATPase (102, 121); 3) BTN2, which encodes a v-SNARE Table 3. Misfolded membrane proteins induce a discrete set of genes required for endosome-to-Golgi trafficking (72) and interacts with the Sis1 (Hsp40) and Hsp42 (sHsp) molecular chaperones (95); and 4) HCH1, which encodes an Hsp90 partner, activates the chaperone's ATPase activity, and regulates cellular sensitivity to Hsp90 inhibitor (5,89,122). Like Hsp90, Hch1 is also heat shock responsive, and Hsp90 stabilizes both CFTR and Ste6* in yeast and human cells (88,111,167).…”