Activity Regulation and Conformation Response of Janus Kinase 3 Mediated by Phosphorylation: Exploration from Correlation Network Analysis and Markov Model.

Abstract

The activity of the enzyme JAK3 is modulated by tyrosine phosphorylation, yet the underlying molecular details remain not fully understood. In this study, we employed a GaMD trajectory-based Markov model and correlation network analysis (CNA) to investigate the impact of single phosphorylation (SP) at Y980 (pY980) and double phosphorylation (DP) at Y980/Y981 (pY980/pY981) on the conformational dynamics of JAK3 bound by inhibitors IZA and MI1. The Markov model analysis indicated that both SP and DP result in fewer conformational states and significantly influence the conformational dynamics of the P-loop, αC-helix, and loop1-loop3, while maintaining the hinge region's high rigidity. The CNA findings revealed that phosphorylation alters the communication network among different structural regions of JAK3, providing a rational explanation for how phosphorylation affects the conformational dynamics of the distant P-loop and loop1-loop3. Moreover, the conformational changes mediated by SP and DP further affect the interactions between the inhibitors and the hot spots (L828, V836, E903, Y904, L905, and L956) of JAK3. This work offers valuable theoretical insights into the molecular mechanisms that regulate JAK3 activity.