The essential co-chaperone Sgt1 regulates client dwell time in the Hsp90 chaperone cycle

Abstract

The Hsp90 machinery is the most complex chaperone system in the eukaryotic cell. It is characterized by numerous co-chaperones that modulate the function of Hsp90. In S. cerevisiae, most of these cofactors can be deleted without affecting viability. Of the three essential ones, only the function of Sgt1 remained enigmatic. Our in vivo and in vitro experiments define key structural elements and determine the essential function of Sgt1 in the chaperoning of client proteins. We show that yeast Sgt1 exhibits a unique binding mode to Hsp90. The simultaneous interaction of Sgt1 with Hsp90 and client proteins enhances client maturation efficiency. Specifically, Sgt1 stabilizes Hsp90-client complexes and prevents their dissociation by the co-chaperone Aha1. Together, our findings reveal a distinct regulatory mechanism of the Hsp90 function, highlighting Sgt1 as a critical modulator of chaperone cycle progression.