MenT nucleotidyltransferase toxins extend tRNA acceptor stems and can be inhibited by asymmetrical antitoxin binding

Xibing Xu, Ben Usher, Claude Gutierrez, Roland Barriot, Tom J. Arrowsmith, Xue Han, Peter Redder, Olivier Neyrolles, Tim R. Blower () and Pierre Genevaux ()
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Xibing Xu: Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3)
Ben Usher: Durham University, South Road
Claude Gutierrez: Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3)
Roland Barriot: Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3)
Tom J. Arrowsmith: Durham University, South Road
Xue Han: Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3)
Peter Redder: Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3)
Olivier Neyrolles: Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3)
Tim R. Blower: Durham University, South Road
Pierre Genevaux: Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3)

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Mycobacterium tuberculosis, the bacterium responsible for human tuberculosis, has a genome encoding a remarkably high number of toxin-antitoxin systems of largely unknown function. We have recently shown that the M. tuberculosis genome encodes four of a widespread, MenAT family of nucleotidyltransferase toxin-antitoxin systems. In this study we characterize MenAT1, using tRNA sequencing to demonstrate MenT1 tRNA modification activity. MenT1 activity is blocked by MenA1, a short protein antitoxin unrelated to the MenA3 kinase. X-ray crystallographic analysis shows blockage of the conserved MenT fold by asymmetric binding of MenA1 across two MenT1 protomers, forming a heterotrimeric toxin-antitoxin complex. Finally, we also demonstrate tRNA modification by toxin MenT4, indicating conserved activity across the MenT family. Our study highlights variation in tRNA target preferences by MenT toxins, selective use of nucleotide substrates, and diverse modes of MenA antitoxin activity.

Date: 2023
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DOI: 10.1038/s41467-023-40264-3

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