School of Computational Sciences and Crean School of Health and Life Sciences, Schmid College of Science and Technology, Chapman University , One University Drive, Orange, California 92866, United States.
J Chem Inf Model. 2013 Nov 25;53(11):2962-78. doi: 10.1021/ci400434g. Epub 2013 Nov 12.
A fundamental role of the Hsp90 chaperone system in mediating maturation of protein clients is essential for the integrity of signaling pathways involved in cell cycle control and organism development. Molecular characterization of Hsp90 interactions with client proteins is fundamental to understanding the activity of many tumor-inducing signaling proteins and presents an active area of structural and biochemical studies. In this work, we have probed mechanistic aspects of allosteric regulation of Hsp90 by client proteins via a detailed computational study of Hsp90 interactions with the tumor suppressor protein p53. Experimentally guided protein docking and molecular dynamics structural refinement have reconstructed the recognition-competent states of the Hsp90-p53 complexes that are consistent with the NMR studies. Protein structure network analysis has identified critical interacting networks and specific residues responsible for structural integrity and stability of the Hsp90-p53 complexes. Coarse-grained modeling was used to characterize the global dynamics of the regulatory complexes and map p53-induced changes in the conformational equilibrium of Hsp90. The variations in the functional dynamics profiles of the Hsp90-p53 complexes are consistent with the NMR studies and could explain differences in the functional role of the alternative binding sites. Despite the overall similarity of the collective movements and the same global interaction footprint, p53 binding at the C-terminal interaction site of Hsp90 may have a more significant impact on the chaperone dynamics, which is consistent with the stronger allosteric effect of these interactions revealed by the experimental studies. The results suggest that p53-induced modulation of the global dynamics and structurally stable interaction networks can target the regulatory hinge regions and facilitate stabilization of the closed Hsp90 dimer that underlies the fundamental stimulatory effect of the p53 client.
Hsp90 伴侣蛋白系统在介导蛋白质客户成熟方面的基本作用对于涉及细胞周期控制和生物体发育的信号通路的完整性至关重要。Hsp90 与客户蛋白相互作用的分子特征对于理解许多诱导肿瘤的信号蛋白的活性至关重要，并呈现出结构和生化研究的活跃领域。在这项工作中，我们通过详细研究 Hsp90 与肿瘤抑制蛋白 p53 的相互作用，探讨了客户蛋白对 Hsp90 变构调节的机制方面。实验指导的蛋白质对接和分子动力学结构细化重建了与 NMR 研究一致的 Hsp90-p53 复合物的识别能力状态。蛋白质结构网络分析确定了关键相互作用网络和特定残基，这些网络和残基负责 Hsp90-p53 复合物的结构完整性和稳定性。粗粒化建模用于表征调节复合物的整体动力学，并绘制 p53 诱导的 Hsp90 构象平衡变化。Hsp90-p53 复合物的功能动力学特征的变化与 NMR 研究一致，并可以解释替代结合位点的功能作用的差异。尽管整体运动和相同的全局相互作用足迹相似，但 p53 在 Hsp90 的 C 端相互作用位点的结合可能对伴侣蛋白动力学产生更大的影响，这与实验研究揭示的这些相互作用的更强变构效应一致。结果表明，p53 诱导的全局动力学和结构稳定相互作用网络的调制可以靶向调节铰链区域，并促进基础 p53 客户的封闭 Hsp90 二聚体的稳定化。
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