Substrate recognition and cryo-EM structure of the ribosome-bound TAC toxin of Mycobacterium tuberculosis.

Mansour, Moise; Giudice, Emmanuel; Xu, Xibing; Akarsu, Hatice; Bordes, Patricia; Guillet, Valérie; Bigot, Donna-Joe; Slama, Nawel; D'urso, Gaetano; Chat, Sophie; Redder, Peter; Falquet, Laurent; Mourey, Lionel; Gillet, Reynald; Genevaux, Pierre (2022). Substrate recognition and cryo-EM structure of the ribosome-bound TAC toxin of Mycobacterium tuberculosis. Nature Communications, 13(1), p. 2641. Springer Nature 10.1038/s41467-022-30373-w

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Toxins of toxin-antitoxin systems use diverse mechanisms to control bacterial growth. Here, we focus on the deleterious toxin of the atypical tripartite toxin-antitoxin-chaperone (TAC) system of Mycobacterium tuberculosis, whose inhibition requires the concerted action of the antitoxin and its dedicated SecB-like chaperone. We show that the TAC toxin is a bona fide ribonuclease and identify exact cleavage sites in mRNA targets on a transcriptome-wide scale in vivo. mRNA cleavage by the toxin occurs after the second nucleotide of the ribosomal A-site codon during translation, with a strong preference for CCA codons in vivo. Finally, we report the cryo-EM structure of the ribosome-bound TAC toxin in the presence of native M. tuberculosis cspA mRNA, revealing the specific mechanism by which the TAC toxin interacts with the ribosome and the tRNA in the P-site to cleave its mRNA target.

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