Structural and mutational analysis of MazE6-operator DNA complex provide insights into autoregulation of toxin-antitoxin systems

Of the 10 paralogs of MazEF Toxin-Antitoxin system in Mycobacterium tuberculosis, MazEF6 plays an important role in multidrug tolerance, virulence, stress adaptation and Non Replicative Persistant (NRP) state establishment. The solution structures of the DNA binding domain of MazE6 and of its complex with the cognate operator DNA show that transcriptional regulation occurs by binding of MazE6 to an 18 bp operator sequence bearing the TANNNT motif (-10 region). Kinetics and thermodynamics of association, as determined by NMR and ITC, indicate that the nMazE6-DNA complex is of high affinity. Residues in N-terminal region of MazE6 that are key for its homodimerization, DNA binding specificity, and the base pairs in the operator DNA essential for the protein-DNA interaction, have been identified. It provides a basis for design of chemotherapeutic agents that will act via disruption of TA autoregulation, leading to cell death.

Automated summary

Among the 10 paralogs of the MazEF Toxin-Antitoxin system in Mycobacterium tuberculosis, MazEF6 plays a crucial role in multidrug tolerance, virulence, stress adaptation, and establishment of the Non Replicative Persistant (NRP) state. The study on the solution structures and dynamics of MazE6 and its complex with the cognate operator DNA sheds light on the transcriptional regulation and provides insights for the development of chemotherapeutic agents targeting the MazEF system.