Acetylation of Response Regulator Proteins, TcrX and MtrA in M. tuberculosis Tunes their Phosphotransfer Ability and Modulates Two-Component Signaling Crosstalk.
Acetylation of Response Regulator Proteins, TcrX and MtrA in M. tuberculosis Tunes their Phosphotransfer Ability and Modulates Two-Component Signaling Crosstalk.
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DOI：
10.1016/j.jmb.2019.01.004
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发表时间：
2019-02
影响因子：
5.6
通讯作者：
Krishna K. Singh;Neerupma Bhardwaj;Gaurav D. Sankhe;N. Udaykumar;Rambir Singh;Vandana Malhotra;D. Saini
中科院分区：
文献类型：
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作者：
Krishna K. Singh;Neerupma Bhardwaj;Gaurav D. Sankhe;N. Udaykumar;Rambir Singh;Vandana Malhotra;D. Saini
双组分信号转导（TCS）级联涉及刺激依赖性激活和传感器激酶（SK）的磷酸化，然后将磷酸化部分转移到反应调节（RR）蛋白。这种从SK到RR的磷酸转移反应的保真度为TCS信号传递提供了特异性。在目前的研究中，我们发现对于结核分枝杆菌的转录自动调节的RR TcrX，乙酰化增强了同源SK TcrY的净磷酸化，并降低了非同源SK MtrB的净磷酸化。类似的乙酰化介导的磷酸化增加也在同源的SK MtrB的另一个RR MtrA中观察到。因此，我们建立了一种新的TCS信号设计，其中RRs的乙酰化导致同源磷酸化增强并抑制非同源磷酸化。使用野生型或乙酰化缺陷的TcrX蛋白。我们证明了非乙酰化的TcrX作为MtrB的“磷酸盐汇”，抑制MtrB到MtrAin的信号传播，将代谢与TCS信号联系起来。总的来说，我们报道了RRs的乙酰化可以保护TCS免受串扰，调节磷酸酶活性并改变RRs的dna结合活性，这些都是TCS系统的非直觉行为。
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 inM. tuberculosisH37Ra, we demonstrate that non-acetylated TcrX acts as a “phosphate sink” for MtrB and suppressing signal propagation from MtrB to MtrAin 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.