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Lookup NU author(s): Shangze Xu, Dr Agnieszka Bronowska
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024.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.
Author(s): Arrowsmith TJ, Xu X, Xu S, Usher B, Stokes P, Guest M, Bronowska AK, Genevaux P, Blower TR
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2024
Volume: 15
Issue: 1
Online publication date: 04/09/2024
Acceptance date: 22/08/2024
Date deposited: 17/09/2024
ISSN (electronic): 2041-1723
Publisher: Nature Research
URL: https://doi.org/10.1038/s41467-024-51934-1
DOI: 10.1038/s41467-024-51934-1
Data Access Statement: The crystal structures have been deposited in the Protein Data Bank under accession numbers 8RR5 (MenT1-p) and 8RR6 (MenT3). Other PDB entries used in this study can be found under the following accession numbers: 8AN4 (MenT1); 8AN5 (MenAT1 complex); 6Y5U (MenT3-p); 8XHR (MenT3-CTP); 6Y56 (MenT4); 6Y8Q (AbiEi). All other data needed to evaluate the conclusions in the paper are present in the paper and/or Supplementary Information/Source Data file. Source data are provided with this paper
PubMed id: 39231966
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