A methylated lysine is a switch point for conformational communication in the chaperone Hsp90

Alexandra Rehn, Jannis Lawatscheck, Marie-Lena Jokisch, Sophie L. Mader, Qi Luo, Franziska Tippel, Birgit Blank, Klaus Richter, Kathrin Lang, Ville R. I. Kaila and Johannes Buchner ()
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Alexandra Rehn: Technische Universität München
Jannis Lawatscheck: Technische Universität München
Marie-Lena Jokisch: Technische Universität München
Sophie L. Mader: Technische Universität München
Qi Luo: Technische Universität München
Franziska Tippel: Technische Universität München
Birgit Blank: Technische Universität München
Klaus Richter: Technische Universität München
Kathrin Lang: Technische Universität München
Ville R. I. Kaila: Technische Universität München
Johannes Buchner: Technische Universität München

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15048-8

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