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

Abstract

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.

Structural elements in the flexible tail of the co-chaperone p23 coordinate client binding and progression of the Hsp90 chaperone cycle

“…However, given that the concentration of p23 in the cell is much lower than that of Hsp90, binding of one p23 per Hsp90 forming an asymmetric complex seems physiologically relevant 35 , 42 , 43 . The binding of p23 to Hsp90 leads to a 50% reduction of the ATPase rate 39 – 41 , 44 and to prolonged Hsp90 client association 41 , 45 – 48 .…”

Controlling protein function by fine-tuning conformational flexibility

“…anti-cancer drug candidates ( Schmid et al, 2018 ) or natural nucleotides ( Schmid et al, 2016 ). In addition, to the stress-induced isoform discussed herein (Hsp82), there is also a cognate isoform (Hsc82) in yeast, which differs in unfolding stability, client range and more, despite 97% sequence identity ( Girstmair et al, 2019 ).…”

Mutations in the Hsp90 N Domain Identify a Site that Controls Dimer Opening and Expand Human Hsp90α Function in Yeast

“…Both Saccharomyces cerevisiae and humans have two isoforms of Hsp90, called Hsc82 and Hsp82 in yeast and hHsp90α and hHsp90β in humans [ 14 , 15 ]. Hsc82 and hHsp90β are constitutively expressed and abundant under optimal conditions.…”

“…Levels of Hsp82 and hHsp90α are normally low but induced to high levels under stress. There are minor structural distinctions between Hsc82 and Hsp82, but their interactomes in vivo are essentially identical, with slight differences under stress conditions [ 14 ]. The sequence identity between hHsp90α and hHsp90β (85%) is lower than between yeast Hsp90s (97%).…”