Mechanisms of neutralization of toxSAS from toxin–antitoxin modules

IF 12.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Nature chemical biology Pub Date : 2024-06-04 DOI:10.1038/s41589-024-01630-4

Lucia Dominguez-Molina, Tatsuaki Kurata, Albinas Cepauskas, Dannele Echemendia-Blanco, Safia Zedek, Ariel Talavera-Perez, Gemma C. Atkinson, Vasili Hauryliuk, Abel Garcia-Pino

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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.

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毒素-抗毒素模块中和 toxSAS 的机制

毒性小警戒素合成酶（toxSAS）是存在于毒素-抗毒素和分泌系统中的细菌效应物家族。毒性小警戒素合成酶通过转移核糖核酸（tRNA）CCA末端的焦磷酸化或毒性警戒素五磷酸腺苷（(pp)ppApp）的合成以及三磷酸腺苷（ATP）的耗竭（分别以FaRel2和FaRel为例）来抑制翻译。然而，toxSAS 中和的结构基础尚不存在。在这里，我们发现 ATfaRel2 抗毒素的伪 Zn2+ 手指结构域（pZFD）阻止 ATP 进入 FaRel2 毒素的焦磷酸供体位点，而不影响 tRNA 焦磷酸受体的招募。与此相反，(pp)pp-pApp-producing toxSAS 通过阻塞焦磷酸受体结合位点而受到 Tis1 抗毒素结构域的抑制。因此，AT2faRel 的辅助 pZFD 对于 FaRel 的中和是不可或缺的。总之，我们的研究确立了结构化抗毒素结构域抑制 toxSAS 的一般原理，其控制策略与 toxSAS 底物的特异性直接相关。

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来源期刊

Nature chemical biology 生物-生化与分子生物学

CiteScore

23.90

自引率

1.40%

发文量

238

审稿时长

12 months

期刊介绍： Nature Chemical Biology stands as an esteemed international monthly journal, offering a prominent platform for the chemical biology community to showcase top-tier original research and commentary. Operating at the crossroads of chemistry, biology, and related disciplines, chemical biology utilizes scientific ideas and approaches to comprehend and manipulate biological systems with molecular precision. The journal embraces contributions from the growing community of chemical biologists, encompassing insights from chemists applying principles and tools to biological inquiries and biologists striving to comprehend and control molecular-level biological processes. We prioritize studies unveiling significant conceptual or practical advancements in areas where chemistry and biology intersect, emphasizing basic research, especially those reporting novel chemical or biological tools and offering profound molecular-level insights into underlying biological mechanisms. Nature Chemical Biology also welcomes manuscripts describing applied molecular studies at the chemistry-biology interface due to the broad utility of chemical biology approaches in manipulating or engineering biological systems. Irrespective of scientific focus, we actively seek submissions that creatively blend chemistry and biology, particularly those providing substantial conceptual or methodological breakthroughs with the potential to open innovative research avenues. The journal maintains a robust and impartial review process, emphasizing thorough chemical and biological characterization.