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Mechanisms of neutralization of toxSAS from toxin-antitoxin modules
BiologyNature Chemical Biology

Mechanisms of neutralization of toxSAS from toxin-antitoxin modules

L. Dominguez-molina, T. Kurata, et al.

Discover groundbreaking insights into toxic small alarmone synthetase (toxSAS) enzymes, the bacterial effectors that inhibit translation and deplete ATP. This research, conducted by Lucia Dominguez-Molina and colleagues, uncovers innovative mechanisms of inhibition linking control strategies to substrate specificity.... show more
Abstract
Toxic small alarmone synthetase (toxSAS) enzymes constitute a family of bacterial effectors present in toxin-antitoxin and secretion systems. toxSASs act through either translation inhibition mediated by pyrophosphorylation of transfer RNA (tRNA) CCA ends or synthesis of the toxic alarmone adenosine pentaphosphate ((pp)pApp) and adenosine triphosphate (ATP) depletion, exemplified by FaRel2 and FaRel, respectively. However, structural bases of toxSAS neutralization are missing. Here we show that the pseudo-Zn²⁺ finger domain (pZFD) of the ATfaRel2 antitoxin precludes access of ATP to the pyrophosphate donor site of the FaRel2 toxin, without affecting recruitment of the tRNA pyrophosphate acceptor. By contrast, (pp)pApp-producing toxSASs are inhibited by Tis1 antitoxin domains though occlusion of the pyrophosphate acceptor-binding site. Consequently, the auxiliary pZFD of AT2faRel is dispensable for FaRel neutralization. Collectively, our study establishes the general principles of toxSAS inhibition by structured antitoxin domains, with the control strategy directly coupled to toxSAS substrate specificity.
Publisher
Nature Chemical Biology
Published On
Jun 04, 2024
Authors
Lucia Dominguez-Molina, Tatsuaki Kurata, Albinas Cepauskas, Dannelle Echemendia-Blanco, Safia Zedek, Ariel Talavera-Perez, Gemma C. Atkinson, Vasili Hauryliuk, Abel Garcia-Pino
Tags
toxSAStranslation inhibitiontRNA pyrophosphorylationATP depletionantitoxin
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