Conformational Dynamics of Response Regulator RegX3 from Mycobacterium tuberculosis.

ABSTRACT: Two-component signal transduction systems (TCS) are vital for adaptive responses to various environmental stresses in bacteria, fungi and even plants. A TCS typically comprises of a sensor histidine kinase (SK) with its cognate response regulator (RR), which often has two domains-N terminal receiver domain (RD) and C terminal effector domain (ED). The histidine kinase phosphorylates the RD to activate the ED by promoting dimerization. However, despite significant progress on structural studies, how RR transmits activation signal from RD to ED remains elusive. Here we analyzed active to inactive transition process of OmpR/PhoB family using an active conformation of RegX3 from Mycobacterium tuberculosis as a model system by computational approaches. An inactive state of RegX3 generated from 150 ns molecular dynamic simulation has rotameric conformations of Thr79 and Tyr98 that are generally conserved in inactive RRs. Arg81 in loop ?4?4 acts synergistically with loop ?1?1 to change its interaction partners during active to inactive transition, potentially leading to the N-terminal movement of RegX3 helix ?1. Global conformational dynamics of RegX3 is mainly dependent on ?4?5 region, in particular seven 'hot-spot' residues (Tyr98 to Ser104), adjacent to which several coevolved residues at dimeric interface, including Ile76-Asp96, Asp97-Arg111 and Glu24-Arg113 pairs, are critical for signal transduction. Taken together, our computational analyses suggest a molecular linkage between Asp phosphorylation, proximal loops and ?4?5?5 dimeric interface during RR active to inactive state transition, which is not often evidently defined from static crystal structures.

SUBMITTER: Ahmad A 

PROVIDER: S-EPMC4511772 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature