The Hsp90 isoforms from S. cerevisiae differ in structure, function and client range

The molecular chaperone Hsp90 is an important regulator of proteostasis. It has remained unclear why S. cerevisiae possesses two Hsp90 isoforms, the constitutively expressed Hsc82 and the stress-inducible Hsp82. Here, we report distinct differences despite a sequence identity of 97%. Consistent with its function under stress conditions, Hsp82 is more stable and refolds more efficiently than Hsc82. The two isoforms also differ in their ATPases and conformational cycles. Hsc82 is more processive and populates closed states to a greater extent. Variations in the N-terminal ATP-binding domain modulate its dynamics and conformational cycle. Despite these differences, the client interactomes are largely identical, but isoform-specific interactors exist both under physiological and heat shock conditions. Taken together, changes mainly in the N-domain create a stress-specific, more resilient protein with a shifted activity profile. Thus, the precise tuning of the Hsp90 isoforms preserves the basic mechanism but adapts it to specific needs. S. cerevisiae encodes two Hsp90 isoforms, the constitutively expressed Hsc82 and stress-inducible Hsp82 that are 97% identical. Here, the authors combine a range of biophysical methods and show that they differ in their enzymatic properties, resilience to stress and client range, which suggests that they evolved to provide fine-tuned chaperone assistance under physiological and stress conditions.