Characterization of the motif requirements for the function of Aha1p and its homologue Hch1p
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Abstract
The Hsp90 chaperone facilitates the maturation of client proteins, which are key players in cancer. Hsp90 inhibitor drugs, such as NVP-AUY922, are promising anti-cancer therapies. Co-chaperones regulate the ATPase-dependent Hsp90 activity and specifically, the co-chaperone Aha1 is the most robust stimulator of Hsp90 ATPase activity. Hch1p is a homologue of Aha1p and shares numerous conserved motifs. The conserved RKxK motif is involved in remodeling of the catalytic loop in Hsp90 and is required for Hch1p and Aha1p function. Surprisingly, the highly conserved N terminal peptide NxxNWHW is required for Hch1p activity in vivo but not for ATPase stimulation by either co-chaperone in vitro. Interestingly, Hch1p regulates sensitivity to Hsp90 inhibitor drugs in vivo whereas Aha1p does not. I propose that Hch1p regulates a step distinct than that of Aha1p which occurs early in the Hsp90 cycle and is sensitive to drug inhibition.