Understanding molecular principles underlying chaperone-based modulation of kinase client activity is critically important to dissect functions and activation mechanisms of many oncogenic proteins. The recent experimental studies have suggested that phosphorylation sites in the Hsp90 and Cdc37 proteins can serve as conformational communication switches of chaperone regulation and kinase interactions. However, a mechanism of allosteric coupling between phosphorylation sites in the Hsp90 and Cdc37 during client binding is poorly understood, and the molecular signatures underpinning specific roles of phosphorylation sites in the Hsp90 regulation remain unknown. In this work, we employed a combination of evolutionary analysis, coarse-grained molecular simulations together with perturbation-based network modeling and scanning of the unbound and bound Hsp90 and Cdc37 structures to quantify allosteric effects of phosphorylation sites and identify unique signatures that are characteristic for communication switches of kinase-specific client binding. By using network-based metrics of the dynamic intercommunity bridgeness and community centrality, we characterize specific signatures of phosphorylation switches involved in allosteric regulation. Through perturbation-based analysis of the dynamic residue interaction networks, we show that mutations of kinase-specific phosphorylation switches can induce long-range effects and lead to a global rewiring of the allosteric network and signal transmission in the Hsp90-Cdc37-kinase complex. We determine a specific group of phosphorylation sites in the Hsp90 where mutations may have a strong detrimental effect on allosteric interaction network, providing insight into the mechanism of phosphorylation-induced communication switching. The results demonstrate that kinase-specific phosphorylation switches of communications in the Hsp90 may be partly predisposed for their regulatory role based on preexisting allosteric propensities.

中文翻译：

---

通过磷酸化位点的变构偶联，探索具有客户激酶的Hsp90-Cdc37调控复合物中的通信交换机制：基于扰动的建模和残基相互作用网络的分层社区分析。

理解基于伴侣的激酶客户活性调节的分子原理对于剖析许多致癌蛋白的功能和激活机制至关重要。最近的实验研究表明，Hsp90和Cdc37蛋白中的磷酸化位点可以充当伴侣调节和激酶相互作用的构象通信开关。但是，客户绑定过程中Hsp90和Cdc37中的磷酸化位点之间的变构偶联机制尚不甚了解，而支持Hsp90调控中的磷酸化位点的特定作用的分子标记仍然未知。在这项工作中，我们结合了进化分析，粗粒分子模拟，以及基于扰动的网络建模以及对未结合和结合的Hsp90和Cdc37结构的扫描，以量化磷酸化位点的变构效应，并识别独特的特征，这些特征是特定于激酶的客户结合的通讯开关的特征。通过使用基于网络的动态社区间桥梁性和社区中心性的指标，我们表征了变构调节中磷酸化开关的特定特征。通过对动态残基相互作用网络进行基于扰动的分析，我们表明激酶特异性磷酸化开关的突变可诱导远程效应，并导致变构网络的全局重新布线以及Hsp90-Cdc37-激酶复合物中的信号传输。我们确定了Hsp90中特定的一组磷酸化位点，其中的突变可能会对变构相互作用网络产生强烈的不利影响，从而提供了对磷酸化诱导的通讯转换机制的深入了解。结果表明，基于预先存在的变构倾向，Hsp90中通讯的激酶特异性磷酸化开关可能会部分地发挥其调节作用。