Abstract
Methylation of a conserved lysine in C-terminal domain of the molecular chaperone Hsp90 was shown previously to affect its in vivo function. However, the underlying mechanism remained elusive. Through a combined experimental and computational approach, this study shows that this site is very sensitive to sidechain modifications and crucial for Hsp90 activity in vitro and in vivo. Our results demonstrate that this particular lysine serves as a switch point for the regulation of Hsp90 functions by influencing its conformational cycle, ATPase activity, co-chaperone regulation, and client activation of yeast and human Hsp90. Incorporation of the methylated lysine via genetic code expansion specifically shows that upon modification, the conformational cycle of Hsp90 is altered. Molecular dynamics simulations including the methylated lysine suggest specific conformational changes that are propagated through Hsp90. Thus, methylation of the C-terminal lysine allows a precise allosteric tuning of Hsp90 activity via long distances.
Highlights
Methylation of a conserved lysine in C-terminal domain of the molecular chaperone Hsp[90] was shown previously to affect its in vivo function
Hsp[90] is a dimeric protein, in which each protomer consists of three domains: an N-terminal domain (NTD) containing the ATP binding pocket, a middle domain important for client and co-chaperone interaction, and a C-terminal dimerization domain (CTD)[12,13,14]
We discovered that the methylation position is a switch point in Hsp[90] conserved from yeast to man and modulates conserved Hsp[90] functions
Summary
Methylation of a conserved lysine in C-terminal domain of the molecular chaperone Hsp[90] was shown previously to affect its in vivo function. Our results demonstrate that this particular lysine serves as a switch point for the regulation of Hsp[90] functions by influencing its conformational cycle, ATPase activity, co-chaperone regulation, and client activation of yeast and human Hsp[90]. Hsp[90] is a highly conserved molecular chaperone in the cytoplasm of eukaryotic cells It is responsible for the folding, activation, and maturation of several hundred client proteins[1,2]. Some positions targeted by PTMs have been shown to represent conformational switch points where a small modification can decisively change the properties of Hsp[90] in an allosteric manner[23,28,33]. We discovered that the methylation position is a switch point in Hsp[90] conserved from yeast to man and modulates conserved Hsp[90] functions
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