Acetylation of Response Regulator Proteins, TcrX and MtrA in M. tuberculosis Tunes their Phosphotransfer Ability and Modulates Two-Component Signaling Crosstalk

Singh, KK and Bhardwaj, N and Sankhe, GD and Udaykumar, N and Singh, R and Malhotra, V and Saini, DK (2019) Acetylation of Response Regulator Proteins, TcrX and MtrA in M. tuberculosis Tunes their Phosphotransfer Ability and Modulates Two-Component Signaling Crosstalk. In: Journal of Molecular Biology, 431 (4). pp. 777-793.

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Abstract

Two-component signal transduction (TCS) cascades involve stimulus-dependent activation and phosphorylation of a sensor kinase (SK), which then transfers the phosphoryl moiety to the response regulator (RR) protein. The fidelity of this phosphotransfer reaction from the SK to the RR provides specificity to TCS signaling. In the present study, we show that for TcrX, a transcriptionally autoregulated RR of Mycobacterium tuberculosis, acetylation enhances its net phosphorylation from cognate SK TcrY and lowers it from a non-cognate SK MtrB. Similar acetylation mediated increase in phosphorylation was also observed for another RR MtrA from cognate SK MtrB. Thus, we establish a novel TCS signaling design wherein acetylation of RRs results in enhanced cognate phosphorylation and suppresses non-cognate phosphorylation. Using wild-type or acetylation-deficient TcrX proteins in M. tuberculosis H37Ra, we demonstrate that non-acetylated TcrX acts as a “phosphate sink” for MtrB and suppressing signal propagation from MtrB to MtrA in vivo, linking metabolism to TCS signaling. Overall, we report that acetylation of RRs shields TCSs from crosstalk, modulates the phosphatase activities and alters the DNA-binding activities of RRs, all of which are non-intuitive behavior of TCS systems.

Item Type:	Journal Article
Publication:	Journal of Molecular Biology
Publisher:	Academic Press
Additional Information:	The copyright for this article belongs to Academic Press
Keywords:	bacterial protein; MtrA protein; TcrX protein; unclassified drug; bacterial protein; phosphotransferase, Article; autoregulation; bacterial metabolism; controlled study; genet (clone); in vivo study; molecular interaction; Mycobacterium tuberculosis; nonhuman; priority journal; protein acetylation; protein function; protein phosphorylation; protein transport; signal transduction; transcription regulation; acetylation; genetic transcription; genetics; homeostasis; phosphorylation; signal transduction, Acetylation; Bacterial Proteins; Homeostasis; Mycobacterium tuberculosis; Phosphorylation; Phosphotransferases; Signal Transduction; Transcription, Genetic
Department/Centre:	Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Date Deposited:	13 Dec 2022 05:07
Last Modified:	13 Dec 2022 05:07
URI:	https://eprints.iisc.ac.in/id/eprint/78333

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