A yeast-based assay reveals a functional defect of the Q488H polymorphism in human Hsp90α

It has been argued that the molecular chaperone Hsp90 guards the organism against genetic variations by stabilizing variant Hsp90 substrate proteins. However, little is known about polymorphisms affecting its own functions. We have followed up on a recent study describing two polymorphisms that alter the amino acid sequences of the two Hsp90 isoforms Hsp90α and Hsp90β. Hsp90 is essential for cell proliferation in the budding yeast Saccharomyces cerevisiae, but the human proteins can replace the endogenous ones. In this growth assay, the variant V656M of Hsp90β was indistinguishable from wild-type. In contrast, the Hsp90α variant Q488H, which carries an alteration of a very highly conserved residue, was severely defective for growth compared to wild-type Hsp90α. Hence, the characteristics of this yeast-based system-simplicity, rapidity, low cost-make it ideal for phenotype screening of polymorphisms in HSP90 and possibly many other human genes.