Journal Article

Conformational dynamics modulate the catalytic activity of the molecular chaperone Hsp90

Luo, Qi, Kaila, Ville R. I., Rutz, Daniel A., Lopez, Abraham, Gamiz-Hernandez, Ana P., Mader, Sophie L., Lawatscheck, Jannis, Buchner, Johannes, Sattler, Michael

2020

Overview

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. The chaperone Hsp90 uses the free energy from ATP hydrolysis to control the folding of client proteins in eukaryotic cells. Here the authors provide mechanistic insights into how its catalytic activity is coupled to conformational changes by combining large-scale molecular simulations with NMR, FRET and SAXS experiments.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/6 / 119/118 / 631/45/173 / 631/45/535/1261 / 631/45/535/1267 / 631/45/535/878 / 631/45/612/1981 / 82/80 / 96/33 / Adenosine triphosphatase / Adenosine Triphosphate - chemistry / Adenosine Triphosphate - metabolism / Animals / Binding sites / Biocatalysis / Catalysis / Catalytic activity / Computer simulation / Coupling (molecular) / Domains / Electrostatic properties / Energy / Enzymatic activity / Experiments / Fluorescence resonance energy transfer / Folding / Free energy / Heat shock proteins / HSP90 Heat-Shock Proteins - chemistry / HSP90 Heat-Shock Proteins - genetics / HSP90 Heat-Shock Proteins - metabolism / Hsp90 protein / Humanities and Social Sciences / Hydrolysis / Ion pairs / Models, Molecular / Molecular Docking Simulation / multidisciplinary / NMR / Nuclear magnetic resonance / Protein Binding / Protein Conformation / Protein Domains / Science / Science (multidisciplinary) / Simulation / Zebrafish - genetics / Zebrafish - metabolism