School of Computational Sciences and Crean School of Health and Life Sciences, Schmid College of Science and Technology, Chapman University, Orange, California, United States of America.
PLoS One. 2013 Aug 19;8(8):e71936. doi: 10.1371/journal.pone.0071936. eCollection 2013.
Allosteric interactions of the molecular chaperone Hsp90 with a large cohort of cochaperones and client proteins allow for molecular communication and event coupling in signal transduction networks. The integration of cochaperones into the Hsp90 system is driven by the regulatory mechanisms that modulate the progression of the ATPase cycle and control the recruitment of the Hsp90 clientele. In this work, we report the results of computational modeling of allosteric regulation in the Hsp90 complexes with the cochaperones p23 and Aha1. By integrating protein docking, biophysical simulations, modeling of allosteric communications, protein structure network analysis and the energy landscape theory we have investigated dynamics and stability of the Hsp90-p23 and Hsp90-Aha1 interactions in direct comparison with the extensive body of structural and functional experiments. The results have revealed that functional dynamics and allosteric interactions of Hsp90 can be selectively modulated by these cochaperones via specific targeting of the regulatory hinge regions that could restrict collective motions and stabilize specific chaperone conformations. The protein structure network parameters have quantified the effects of cochaperones on conformational stability of the Hsp90 complexes and identified dynamically stable communities of residues that can contribute to the strengthening of allosteric interactions. According to our results, p23-mediated changes in the Hsp90 interactions may provide "molecular brakes" that could slow down an efficient transmission of the inter-domain allosteric signals, consistent with the functional role of p23 in partially inhibiting the ATPase cycle. Unlike p23, Aha1-mediated acceleration of the Hsp90-ATPase cycle may be achieved via modulation of the equilibrium motions that facilitate allosteric changes favoring a closed dimerized form of Hsp90. The results of our study have shown that Aha1 and p23 can modulate the Hsp90-ATPase activity and direct the chaperone cycle by exerting the precise control over structural stability, global movements and allosteric communications in Hsp90.
分子伴侣 Hsp90 与大量共伴侣和客户蛋白的变构相互作用允许在信号转导网络中进行分子通讯和事件耦合。共伴侣整合到 Hsp90 系统中是由调节机制驱动的，这些机制调节 ATP 酶循环的进展，并控制 Hsp90 客户的招募。在这项工作中，我们报告了计算建模的结果，该模型研究了 Hsp90 与共伴侣 p23 和 Aha1 形成的复合物中的变构调节。通过整合蛋白质对接、生物物理模拟、变构通讯建模、蛋白质结构网络分析和能量景观理论，我们对 Hsp90-p23 和 Hsp90-Aha1 相互作用的动力学和稳定性进行了研究，与广泛的结构和功能实验进行了直接比较。结果表明，这些共伴侣可以通过特异性靶向调节铰链区域来选择性调节 Hsp90 的功能动力学和变构相互作用，从而限制集体运动并稳定特定伴侣构象。蛋白质结构网络参数量化了共伴侣对 Hsp90 复合物构象稳定性的影响，并确定了对变构相互作用有贡献的动态稳定残基社区。根据我们的结果，p23 介导的 Hsp90 相互作用的变化可能提供“分子刹车”，可以减缓域间变构信号的有效传递，与 p23 在部分抑制 ATP 酶循环中的功能作用一致。与 p23 不同，Aha1 介导的 Hsp90-ATP 酶循环的加速可能是通过调节平衡运动来实现的，这些运动有利于变构变化，有利于 Hsp90 的封闭二聚体形式。我们的研究结果表明，Aha1 和 p23 可以通过对 Hsp90 中的结构稳定性、全局运动和变构通讯施加精确控制，来调节 Hsp90-ATP 酶活性和指导伴侣周期。
