Conformational dynamics modulate the catalytic activity of the molecular chaperone Hsp90

Sophie L. Mader, Abraham Lopez, Jannis Lawatscheck, Qi Luo, Daniel A. Rutz, Ana P. Gamiz-Hernandez, Michael Sattler, Johannes Buchner and Ville R. I. Kaila ()
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Sophie L. Mader: Technical University of Munich
Abraham Lopez: Technical University of Munich
Jannis Lawatscheck: Technical University of Munich
Qi Luo: Technical University of Munich
Daniel A. Rutz: Technical University of Munich
Ana P. Gamiz-Hernandez: Technical University of Munich
Michael Sattler: Technical University of Munich
Johannes Buchner: Technical University of Munich
Ville R. I. Kaila: Technical University of Munich

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract The heat shock protein 90 (Hsp90) is a molecular chaperone that employs the free energy of ATP hydrolysis to control the folding and activation of several client proteins in the eukaryotic cell. To elucidate how the local ATPase reaction in the active site couples to the global conformational dynamics of Hsp90, we integrate here large-scale molecular simulations with biophysical experiments. We show that the conformational switching of conserved ion pairs between the N-terminal domain, harbouring the active site, and the middle domain strongly modulates the catalytic barrier of the ATP-hydrolysis reaction by electrostatic forces. Our combined findings provide a mechanistic model for the coupling between catalysis and protein dynamics in Hsp90, and show how long-range coupling effects can modulate enzymatic activity.

Date: 2020
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DOI: 10.1038/s41467-020-15050-0

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