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

Xu, Xibing; Usher, Ben; Gutierrez, Claude; Barriot, Roland; Arrowsmith, Tom J.; Han, Xue; Redder, Peter; Neyrolles, Olivier; Blower, Tim R.; Genevaux, Pierre

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


Authors

Xibing Xu

Ben Usher

Claude Gutierrez

Roland Barriot

Tom Arrowsmith tom.arrowsmith@durham.ac.uk
PGR Student Doctor of Philosophy

Xue Han

Peter Redder

Olivier Neyrolles

Pierre Genevaux



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.

Journal Article Type Article
Acceptance Date Jul 20, 2023
Online Publication Date Aug 17, 2023
Publication Date 2023
Deposit Date Aug 17, 2023
Publicly Available Date Aug 17, 2023
Journal Nature Communications
Publisher Nature Research
Peer Reviewed Peer Reviewed
Volume 14
Article Number 4644
DOI https://doi.org/10.1038/s41467-023-40264-3
Public URL https://durham-repository.worktribe.com/output/1720149

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