The structural basis of hyperpromiscuity in a core combinatorial network of type II toxin-antitoxin and related phage defense systems.
The structural basis of hyperpromiscuity in a core combinatorial network of type II toxin-antitoxin and related phage defense systems.
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DOI：
10.1073/pnas.2305393120
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发表时间：
2023-08-15
影响因子：
11.1
通讯作者：
Atkinson, Gemma C.
中科院分区：
文献类型：
--
作者：
Ernits, Karin;Saha, Chayan Kumar;Brodiazhenko, Tetiana;Chouhan, Bhanu;Shenoy, Aditi;Buttress, Jessica A.;Duque-Pedraza, Julian J.;Bojar, Veda;Nakamoto, Jose A.;Kurata, Tatsuaki;Egorov, Artyom A.;Shyrokova, Lena;Johansson, Marcus J. O.;Mets, Toomas;Rustamova, Aytan;Dzigurski, Jelisaveta;Tenson, Tanel;Garcia-Pino, Abel;Strahl, Henrik;Elofsson, Arne;Hauryliuk, Vasili;Atkinson, Gemma C.
毒素 - 抗毒素系统是微生物基因组的神秘成分，其生物学功能是数十年来的争论。结构界面的高通量预测，我们发现了TA伴侣交换的进化量表，并确定了毒性效应。毒素：四个TA系统的抗毒素复杂界面，揭示了含Panacea的Pana抗毒素的毒素神经化的进化可延展机制，我们发现TAS在进化上与其他几种噬菌体防御系统相关，将其作用固定为它们作为微生物的重要分子成分的作用战争。
毒素 - 抗毒素（TA）系统是在原核生物中发现的一大批小遗传模块，其移动遗传元素被编码为双蛋白质（两基因）操作因：A毒素和中和抗毒素我们的netflax工具（代表毒素和抗毒素的网络范围），我们对蛋白质TAS进行了大规模的生物信息学分析，揭示了构成核心的互连簇TA样基因对抗毒素的结构基础。抗毒素结构域中的抗毒素。多域抗毒素的谈判是由PAD1，PHD-C和ZFD等其他域介导的，我们假设灵丹妙药是一种调节TA激活的传感器。预测其毒性的潜在机制（例如膜破坏和抑制细胞分裂或蛋白质合成）以及生物学功能（例如反出现的防御），我们已经验证了由Gordonia Phage Kita编码的Rosmerta系统的反义活动，并使用荧光显微镜确认了其预测的膜 - 脱发活性。可以在http://netflax.webflags.s.s.se/上访问。
Toxin–antitoxin systems are enigmatic components of microbial genomes, with their biological functions being a conundrum of debate for decades. Increasingly, TAs are being found to have a role in defense against bacteriophages. By mapping and experimentally validating a core combinatorial network of TA systems and high-throughput prediction of structural interfaces, we uncover the evolutionary scale of TA partner swapping and identify toxic effectors. We validate the predicted toxin:antitoxin complex interfaces of four TA systems, uncovering the evolutionary malleable mechanism of toxin neutralization by Panacea-containing PanA antitoxins. We find TAs are evolutionarily related to several other phage defense systems, cementing their role as important molecular components of the arsenal of microbial warfare. Toxin-antitoxin (TA) systems are a large group of small genetic modules found in prokaryotes and their mobile genetic elements. Type II TAs are encoded as bicistronic (two-gene) operons that encode two proteins: a toxin and a neutralizing antitoxin. Using our tool NetFlax (standing for Network-FlaGs for toxins and antitoxins), we have performed a large-scale bioinformatic analysis of proteinaceous TAs, revealing interconnected clusters constituting a core network of TA-like gene pairs. To understand the structural basis of toxin neutralization by antitoxins, we have predicted the structures of 3,419 complexes with AlphaFold2. Together with mutagenesis and functional assays, our structural predictions provide insights into the neutralizing mechanism of the hyperpromiscuous Panacea antitoxin domain. In antitoxins composed of standalone Panacea, the domain mediates direct toxin neutralization, while in multidomain antitoxins the neutralization is mediated by other domains, such as PAD1, Phd-C, and ZFD. We hypothesize that Panacea acts as a sensor that regulates TA activation. We have experimentally validated 16 NetFlax TA systems and used domain annotations and metabolic labeling assays to predict their potential mechanisms of toxicity (such as membrane disruption, and inhibition of cell division or protein synthesis) as well as biological functions (such as antiphage defense). We have validated the antiphage activity of a RosmerTA system encoded by Gordonia phage Kita, and used fluorescence microscopy to confirm its predicted membrane-depolarizing activity. The interactive version of the NetFlax TA network that includes structural predictions can be accessed at http://netflax.webflags.se/.
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