Mechanisms of neutralization of toxSAS from toxin-antitoxin modules
(2024) In Nature Chemical Biology- 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-Zn
2+ 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... (More)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-Zn
(Less)
2+ 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.
- author
- Dominguez-Molina, Lucia ; Kurata, Tatsuaki LU ; Cepauskas, Albinas ; Echemendia-Blanco, Dannele ; Zedek, Safia ; Talavera-Perez, Ariel ; Atkinson, Gemma C LU ; Hauryliuk, Vasili LU and Garcia-Pino, Abel
- organization
- publishing date
- 2024-06-04
- type
- Contribution to journal
- publication status
- epub
- subject
- in
- Nature Chemical Biology
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85195207967
- pmid:38834893
- ISSN
- 1552-4469
- DOI
- 10.1038/s41589-024-01630-4
- language
- English
- LU publication?
- yes
- additional info
- © 2024. The Author(s).
- id
- 401eecda-805d-497b-8752-693de52ba1e5
- date added to LUP
- 2024-06-09 11:20:35
- date last changed
- 2024-06-24 06:04:03
@article{401eecda-805d-497b-8752-693de52ba1e5, abstract = {{<p>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-Zn<br> 2+ 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.<br> </p>}}, author = {{Dominguez-Molina, Lucia and Kurata, Tatsuaki and Cepauskas, Albinas and Echemendia-Blanco, Dannele and Zedek, Safia and Talavera-Perez, Ariel and Atkinson, Gemma C and Hauryliuk, Vasili and Garcia-Pino, Abel}}, issn = {{1552-4469}}, language = {{eng}}, month = {{06}}, publisher = {{Nature Publishing Group}}, series = {{Nature Chemical Biology}}, title = {{Mechanisms of neutralization of toxSAS from toxin-antitoxin modules}}, url = {{http://dx.doi.org/10.1038/s41589-024-01630-4}}, doi = {{10.1038/s41589-024-01630-4}}, year = {{2024}}, }