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.
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; Department of Pharmacology, University of California San Diego, La Jolla, California, United States of America.
PLoS Comput Biol. 2014 Jun 12;10(6):e1003679. doi: 10.1371/journal.pcbi.1003679. eCollection 2014 Jun.
A fundamental role of the Hsp90 chaperone in regulating functional activity of diverse protein clients is essential for the integrity of signaling networks. In this work we have combined biophysical simulations of the Hsp90 crystal structures with the protein structure network analysis to characterize the statistical ensemble of allosteric interaction networks and communication pathways in the Hsp90 chaperones. We have found that principal structurally stable communities could be preserved during dynamic changes in the conformational ensemble. The dominant contribution of the inter-domain rigidity to the interaction networks has emerged as a common factor responsible for the thermodynamic stability of the active chaperone form during the ATPase cycle. Structural stability analysis using force constant profiling of the inter-residue fluctuation distances has identified a network of conserved structurally rigid residues that could serve as global mediating sites of allosteric communication. Mapping of the conformational landscape with the network centrality parameters has demonstrated that stable communities and mediating residues may act concertedly with the shifts in the conformational equilibrium and could describe the majority of functionally significant chaperone residues. The network analysis has revealed a relationship between structural stability, global centrality and functional significance of hotspot residues involved in chaperone regulation. We have found that allosteric interactions in the Hsp90 chaperone may be mediated by modules of structurally stable residues that display high betweenness in the global interaction network. The results of this study have suggested that allosteric interactions in the Hsp90 chaperone may operate via a mechanism that combines rapid and efficient communication by a single optimal pathway of structurally rigid residues and more robust signal transmission using an ensemble of suboptimal multiple communication routes. This may be a universal requirement encoded in protein structures to balance the inherent tension between resilience and efficiency of the residue interaction networks.
Hsp90 伴侣在调节各种蛋白质客户功能活性方面的基本作用对于信号网络的完整性至关重要。在这项工作中，我们将 Hsp90 晶体结构的生物物理模拟与蛋白质结构网络分析相结合，以表征 Hsp90 伴侣中变构相互作用网络和通信途径的统计集合。我们发现，在构象集合的动态变化过程中，可以保留主要结构稳定的社区。结构域间刚性对相互作用网络的主要贡献已成为在 ATP 酶循环中负责活性伴侣形式热力学稳定性的共同因素。使用互残基波动距离的力常数剖析进行结构稳定性分析，确定了一个保守的结构刚性残基网络，可作为变构通信的全局介导位点。使用网络中心性参数对构象景观进行映射，证明了稳定的社区和介导残基可能与构象平衡的变化协同作用，并可以描述大多数功能重要的伴侣残基。网络分析揭示了参与伴侣调节的热点残基的结构稳定性、全局中心性和功能意义之间的关系。我们发现 Hsp90 伴侣中的变构相互作用可能由结构稳定的残基模块介导，这些残基在全局相互作用网络中具有较高的介数。这项研究的结果表明，Hsp90 伴侣中的变构相互作用可能通过一种机制发挥作用，该机制结合了结构刚性残基的单个最佳路径的快速和有效的通信，以及使用多个次优通信路径的集合的更稳健的信号传输。这可能是蛋白质结构中编码的普遍要求，以平衡残基相互作用网络的弹性和效率之间的固有紧张关系。
