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

Moise Mansour (1) , Emmanuel Giudice (2) , Xibing Xu (1) , Hatice Akarsu (3, 4) , Patricia Bordes (1) , Valérie Guillet (5) , Donna-Joe Bigot (5, 1) , Nawel Slama (1) , Gaetano D’urso (2) , Sophie Chat (2) , Peter Redder (1) , Laurent Falquet (3) , Lionel Mourey (5) , Reynald Gillet (2) , Pierre Genevaux (1)

1 CBI - Centre de Biologie Intégrative
2 IGDR - Institut de Génétique et Développement de Rennes
3 UNIFR - Université de Fribourg = University of Fribourg
4 UNIBE - Universität Bern / University of Bern
5 IPBS - Institut de pharmacologie et de biologie structurale

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.

Domaines: Sciences du Vivant [q-bio]; Génétique

Moise Mansour, Emmanuel Giudice, Xibing Xu, Hatice Akarsu, Patricia Bordes, et al.. Substrate recognition and cryo-EM structure of the ribosome-bound TAC toxin of Mycobacterium tuberculosis. Nature Communications, 2022, 13 (1), pp.2641. ⟨10.1038/s41467-022-30373-w⟩. ⟨hal-03751990⟩