Center for Integrated Protein Science Munich at the Department of Chemistry, Technical University of Munich, Lichtenbergstrasse 4, D85748, Garching, Germany.
Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, Neuherberg, 85764, Germany.
Nat Commun. 2020 Mar 16;11(1):1410. doi: 10.1038/s41467-020-15050-0.
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.
热休克蛋白 90（Hsp90）是一种分子伴侣，它利用 ATP 水解的自由能来控制真核细胞中几种客户蛋白的折叠和激活。为了阐明活性部位的局部 ATP 酶反应如何与 Hsp90 的整体构象动力学偶联，我们在这里将大规模分子模拟与生物物理实验相结合。我们表明，位于含有活性部位的 N 端结构域和中间结构域之间的保守离子对的构象转换通过静电力强烈调节 ATP 水解反应的催化势垒。我们的综合研究结果为 Hsp90 中催化和蛋白质动力学之间的偶联提供了一个机械模型，并展示了远程偶联效应如何调节酶活性。
