Inducible auto-phosphorylation regulates a widespread family of nucleotidyltransferase toxins

Tom J. Arrowsmith, Xibing Xu, Shangze Xu, Ben Usher, Peter Stokes, Megan Guest, Agnieszka K. Bronowska, Pierre Genevaux () and Tim R. Blower ()
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Tom J. Arrowsmith: Durham University
Xibing Xu: Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3)
Shangze Xu: Newcastle University
Ben Usher: Durham University
Peter Stokes: Durham University
Megan Guest: Durham University
Agnieszka K. Bronowska: Newcastle University
Pierre Genevaux: Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3)
Tim R. Blower: Durham University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Nucleotidyltransferases (NTases) control diverse physiological processes, including RNA modification, DNA replication and repair, and antibiotic resistance. The Mycobacterium tuberculosis NTase toxin family, MenT, modifies tRNAs to block translation. MenT toxin activity can be stringently regulated by diverse MenA antitoxins. There has been no unifying mechanism linking antitoxicity across MenT homologues. Here we demonstrate through structural, biochemical, biophysical and computational studies that despite lacking kinase motifs, antitoxin MenA1 induces auto-phosphorylation of MenT1 by repositioning the MenT1 phosphoacceptor T39 active site residue towards bound nucleotide. Finally, we expand this predictive model to explain how unrelated antitoxin MenA3 is similarly able to induce auto-phosphorylation of cognate toxin MenT3. Our study reveals a conserved mechanism for the control of tuberculosis toxins, and demonstrates how active site auto-phosphorylation can regulate the activity of widespread NTases.

Date: 2024
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DOI: 10.1038/s41467-024-51934-1

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