Structural and Biochemical Characterization of the Cognate and Heterologous Interactions of the MazEF-mt9 TA System
Structural and Biochemical Characterization of the Cognate and Heterologous Interactions of the MazEF-mt9 TA System
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MazEF-mt9 TA 系统同源和异源相互作用的结构和生化表征
DOI：
10.1021/acsinfecdis.9b00001
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发表时间：
2019-08-01
影响因子：
5.3
通讯作者：
Xie, Wei
中科院分区：
文献类型：
--
作者：
Chen, Ran;Tu, Jie;Xie, Wei
毒素-抗毒素(TA)模块广泛存在于细菌中，其活性与结核分枝杆菌(M.TB)的持久表型有关。结核分枝杆菌会导致肺结核，这是一种严重的空气传播传染病。结核分枝杆菌中有10个MazEF TA系统在压力适应中发挥重要作用。抗毒素如何对抗结核分枝杆菌中的毒素，以及10个TA系统如何相互串扰是令人感兴趣的，但详细的分子机制在很大程度上尚不清楚。MazEF-mt9是MazEF家族中唯一的成员，由于其tRNase活性，通常由VapC毒素执行。在这里，我们给出了MazEF-mt9络合物在2.7埃的共晶结构。通过不同的技术表征TA对之间的结合模式，我们发现MazF-mt9不仅与其同源抗毒素结合，而且还与非同源抗毒素迷宫-MT1结合，这一现象在体内也可以观察到。基于我们的结构和生化工作，我们认为不同TA系统之间的同源和异源相互作用在体内共同作用，从而减轻了MazF-mt9对结核分枝杆菌细胞的毒性。
Toxin-antitoxin (TA) modules widely exist in bacteria, and their activities are associated with the persister phenotype of the pathogen Mycobacterium tuberculosis (M. tb). M. tb causes tuberculosis, a contagious and severe airborne disease. There are 10 MazEF TA systems in M. tb that play important roles in stress adaptation. How the antitoxins antagonize toxins in M. tb or how the 10 TA systems crosstalk to each other are of interest, but the detailed molecular mechanisms are largely unclear. MazEF-mt9 is a unique member among the MazEF family due to its tRNase activity, which is usually carried out by the VapC toxins. Here, we present the cocrystal structure of the MazEF-mt9 complex at 2.7 angstrom. By characterizing the association mode between the TA pairs through various techniques, we found that MazF-mt9 bound not only its cognate antitoxin but also the noncognate antitoxin MazE-mt1, a phenomenon that could be also observed in vivo. Based on our structural and biochemical work, we propose that the cognate and heterologous interactions among different TA systems work together in vivo to relieve the toxicity of MazF-mt9 toward M. tb cells.