Graduate Program in Computational and Data Sciences, Department of Computational Sciences, Schmid College of Science and Technology, Chapman University , One University Drive, Orange, California 92866, United States.
Chapman University School of Pharmacy , Irvine, California 92618, United States.
J Chem Inf Model. 2018 Feb 26;58(2):405-421. doi: 10.1021/acs.jcim.7b00638. Epub 2018 Feb 15.
A fundamental role of the Hsp90-Cdc37 chaperone machinery in mediating conformational development and activation of diverse protein kinase clients is essential for signal transduction. Structural and biochemical studies have demonstrated that characterization of global conformational changes and allosteric interactions in the Hsp90-Cdc37-kinase complexes are central to our understanding of the mechanisms underlying kinase recruitment and processing by the Hsp90-Cdc37 chaperone. The recent cryo-electron microscopy structure of the Hsp90-Cdc37-Cdk4 kinase complex has provided a framework for dissecting regulatory principles underlying differentiation and recruitment of protein kinase clients to the chaperone machinery. In this work, we have characterized functional role and hierarchy of the intermolecular interactions in binding of protein kinase clients to the Hsp90-Cdc37 system. The network analysis revealed important relationships between structural stability, global centrality, and functional significance of regulatory hotspots in chaperone regulation and client recognition. A unique asymmetric topography of the intermolecular communities in the chaperone-kinase complex has quantified a central mediating role of Cdc37 in client recognition and allosteric regulation of the chaperone-kinase complex. Modeling of allosteric pathways in the chaperone complex has further clarified structural and energetic signatures of allosteric hotspots, particularly linking sites of post-translational modifications in Hsp90 with their role in allosteric interactions and client regulation. The results of this integrative computational study are compared with a wide range of structural, biochemical, and cell-based experiments, offering a robust network-centric model of allosteric regulation and client kinase recognition by the Hsp90-Cdc37 chaperone machine.
Hsp90-Cdc37 伴侣机制在介导多种蛋白激酶客户的构象发育和激活方面的基本作用对于信号转导至关重要。结构和生化研究表明，对 Hsp90-Cdc37-激酶复合物中全局构象变化和变构相互作用的特征描述是理解激酶募集和 Hsp90-Cdc37 伴侣加工机制的核心。最近 Hsp90-Cdc37-Cdk4 激酶复合物的低温电子显微镜结构为剖析蛋白激酶客户与伴侣机制区分和募集的调节原理提供了一个框架。在这项工作中，我们已经确定了蛋白激酶客户与 Hsp90-Cdc37 系统结合的分子间相互作用的功能作用和层次结构。网络分析揭示了伴侣调节和客户识别中监管热点的结构稳定性、全局中心性和功能意义之间的重要关系。伴侣-激酶复合物中分子间社区的独特不对称拓扑结构定量了 Cdc37 在客户识别和伴侣-激酶复合物的变构调节中的核心介导作用。伴侣复合物中变构途径的建模进一步阐明了变构热点的结构和能量特征，特别是将 Hsp90 中翻译后修饰的位点与其在变构相互作用和客户调节中的作用联系起来。这种综合计算研究的结果与广泛的结构、生化和基于细胞的实验进行了比较，为 Hsp90-Cdc37 伴侣机器的变构调节和客户激酶识别提供了一个稳健的网络中心模型。
