Engler, S.; Delhommel, F.; Dodt, C.; Lopez, A.; Faust, O.; Napolitano, V.; Popowicz, G. M.; Rosenzweig, R.; Sattler, M.; Buchner, J.

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 remains to be discovered. Our in vivo and in vitro experiments define key structural elements that determine the essential function of Sgt1 in the context of Hsp90. We show that yeast Sgt1 exhibits a unique binding mode to Hsp90 distinct from other Sgt1 homologs. 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 inhibiting the binding of the Hsp90 to the co-chaperone Aha1. Our findings reveal a novel regulatory mechanism of Hsp90 function, highlighting Sgt1 as a critical modulator of client stability and folding.