Exploring Mechanisms of Communication Switching in the Hsp90-Cdc37 Regulatory Complexes with Client Kinases through Allosteric Coupling of Phosphorylation Sites: Perturbation-Based Modeling and Hierarchical Community Analysis of Residue Interaction Networks

Abstract

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.

Molecular Simulations and Network Modeling Reveal an Allosteric Signaling in the SARS-CoV-2 Spike Proteins

“… 33 The important result of this analysis was a revelation that key regulatory sites that could dictate dynamic switching between conformational states of the SARS-CoV-2 spike trimer overlap with the high-centrality mediators of the interaction network that are also predicted to be effector centers with high allosteric potential ( Figures 10 and 11 ). To further examine the network properties, the hierarchical multilayer community decomposition was performed, and the community centrality metric 118 of the residue interaction networks was computed for distinct functional states of the SARS-CoV-2 spike trimer ( Figure 12 ). The community centrality profile revealed that network hubs that could bridge local modules in the locked state are located at the borders of the RBD regions ( Figures 12 A and 13 A).…”

Post-translational modifications of Hsp90 and translating the chaperone code

“…Further, ATP binding is impacted by CK2 phosphorylation of the Hsp90b charged linker, which has been suggested to precede Hsp90: Cdc37 complex dissociation when ATP levels are low (84). Interestingly, CK2 phosphorylation of Cdc37-S13 promotes its association with kinases and recruitment of Hsp90 to kinase: Cdc37:Hsp90 ternary complexes for the chaperoning of kinase clients (46)(47)(48)152). Furthermore, sequential and ordered phosphorylation of the co-chaperone folliculin-interacting protein 1 (FNIP1) on several adjacent serine residues promotes its binding to Hsp90 and facilitates kinase and nonkinase client chaperoning (153).…”

[Retracted] Security Control Technology and Simulation of Network News Communication under the Environment of Internet of Things

“…This paper studies the self-healing system based on the structural model, summarizes the basic elements that the dynamic fault repair system needs, describes the formal language of the structural model, gives the application tools and related technical specifications, and gives the self-recovery flow diagram of the system. In view of the software development of an embedded system and the application of the structural model, the structure description of platform-dependent and platform-independent parts is given, and the realization of instantaneous fault recovery of the structural model in an embedded system is introduced with application cases [20,21]. Zavala et al [22] introduce the requirement of structural model style for a self-healing system and the method of a self-healing system based on style.…”