Lucia Dominguez-Molina, Tatsuaki Kurata, Albinas Cepauskas, Dannele Echemendia-Blanco, Safia Zedek, Ariel Talavera-Perez, Gemma C. Atkinson, Vasili Hauryliuk, Abel Garcia-Pino
{"title":"毒素-抗毒素模块中和 toxSAS 的机制","authors":"Lucia Dominguez-Molina, Tatsuaki Kurata, Albinas Cepauskas, Dannele Echemendia-Blanco, Safia Zedek, Ariel Talavera-Perez, Gemma C. Atkinson, Vasili Hauryliuk, Abel Garcia-Pino","doi":"10.1038/s41589-024-01630-4","DOIUrl":null,"url":null,"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<sup>2+</sup> 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.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":12.9000,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Mechanisms of neutralization of toxSAS from toxin–antitoxin modules\",\"authors\":\"Lucia Dominguez-Molina, Tatsuaki Kurata, Albinas Cepauskas, Dannele Echemendia-Blanco, Safia Zedek, Ariel Talavera-Perez, Gemma C. Atkinson, Vasili Hauryliuk, Abel Garcia-Pino\",\"doi\":\"10.1038/s41589-024-01630-4\",\"DOIUrl\":null,\"url\":null,\"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<sup>2+</sup> 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.</p><figure></figure>\",\"PeriodicalId\":18832,\"journal\":{\"name\":\"Nature chemical biology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":12.9000,\"publicationDate\":\"2024-06-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature chemical biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1038/s41589-024-01630-4\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature chemical biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41589-024-01630-4","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Mechanisms of neutralization of toxSAS from toxin–antitoxin modules
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.
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