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Biochemical and Structural Characterization of the Carbohydrate Transport Substrate-binding-protein SP0092
Published on: October 2, 2017
Structural and Biochemical Characterization of the Cognate and Heterologous Interactions of the MazEF-mt9 TA System
Ran Chen1, Jie Tu1, Yaoju Tan2
1MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences , The Sun Yat-Sen University , 135 W. Xingang Road , Guangzhou , Guangdong 510006 , People's Republic of China.
Abstract:
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 Å. 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.
Insights
Toxin-antitoxin systems in Mycobacterium tuberculosis help it survive stress. This study reveals how MazEF-mt9 interacts with other antitoxins, offering new insights into tuberculosis persistence.
Area of Science:
- Microbiology
- Structural Biology
- Molecular Mechanisms
Background:
- Toxin-antitoxin (TA) modules are crucial for bacterial survival and stress adaptation.
- Mycobacterium tuberculosis (M. tb), the causative agent of tuberculosis, possesses 10 MazEF TA systems implicated in persistence.
- The precise molecular mechanisms of antitoxin antagonism and TA system crosstalk in M. tb remain largely unelucidated.
Purpose of the Study:
- To elucidate the molecular mechanisms of interaction within the MazEF-mt9 toxin-antitoxin system in M. tb.
- To investigate the unique tRNase activity of MazEF-mt9 and its interactions with cognate and non-cognate antitoxins.
- To understand how crosstalk between different TA systems contributes to M. tb survival under stress.
Main Methods:
- Cocrystallization of the MazEF-mt9 complex.
- X-ray crystallography at 2.7 Å resolution.
- Biochemical characterization of toxin-antitoxin interactions.
Main Results:
- The study determined the cocrystal structure of the MazEF-mt9 complex.
- MazF-mt9 was found to bind to both its cognate antitoxin and the non-cognate antitoxin MazE-mt1.
- This heterologous binding was confirmed to occur in vivo, indicating functional crosstalk.
Conclusions:
- The structural and biochemical data provide a molecular basis for MazEF-mt9 interactions.
- Cognate and heterologous interactions among TA systems are proposed to mitigate MazF-mt9 toxicity in M. tb.
- These findings offer novel insights into the complex regulatory network governing M. tb persistence and stress adaptation.
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