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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Selective interaction between nonribosomal peptide synthetases is facilitated by short communication-mediating domains.
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Selective interaction between nonribosomal peptide synthetases is facilitated by short communication-mediating domains.

机译：非核糖体肽合成酶之间的选择性相互作用可通过短的介导介导的域来促进。

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摘要

Nonribosomal peptide synthetases (NRPSs) catalyze the formation of structurally diverse and biologically important peptides. Given their modular organization, NRPSs provide an enormous potential for biocombinatorial approaches to generate novel bioactive compounds. Crucial for the exploitation of this potential is a profound knowledge of the intermolecular communication between partner NRPSs. The overall goal of this study was to understand the basis of protein-protein communication that facilitates the selective interaction in these multienzyme complexes. On this account, we studied the relevance of short regions at the termini of the NRPSs tyrocidine (Tyc) synthetases TycA, TycB, and TycC, constituting the Tyc biosynthetic template. In vitro and in vivo investigations of C-terminal deletion mutants of the initiation module TycA provided evidence for the existence and impact of short communication-mediating (COM) domains. Their decisive role in protein-protein recognition was subsequently proven by means of COM domain-swapping experiments. Substitution of the terminal COM domains between the donor modules TycA and TycB3, as well as between the acceptor modules TycB1 and TycC1, clearly demonstrated that matching pairs of COM domains are both necessary and sufficient for the establishment of communication between partner NRPSs in trans. These results corroborated the generality of COM domains, which were subsequently exploited to induce crosstalk, even between NRPSs derived from different biosynthetic systems. In conclusion, COM domains represent interesting tools for biocombinatorial approaches, which, for example, could be used for the generation of innovative natural product derivatives.
机译：非核糖体肽合成酶（NRPS）催化结构多样且生物学上重要的肽的形成。鉴于其模块化的组织结构，NRPS为生物组合方法产生新的生物活性化合物提供了巨大的潜力。开发这种潜力的关键是对伙伴NRPS之间的分子间通讯的深入了解。这项研究的总体目标是了解促进这些多酶复合物中的选择性相互作用的蛋白质-蛋白质通讯的基础。因此，我们研究了组成TYC生物合成模板的NRPS酪氨酸（Tyc）合成酶TycA，TycB和TycC末端的短区域的相关性。起始模块TycA的C端缺失突变体的体外和体内研究为短通信介导（COM）域的存在和影响提供了证据。随后通过COM域交换实验证明了它们在蛋白质识别中的决定性作用。供体模块TycA和TycB3之间以及受体模块TycB1和TycC1之间的终端COM域的替换清楚地表明，配对的COM域对对于在跨伙伴NRPS之间建立通信既是必要的又是足够的。这些结果证实了COM域的普遍性，随后甚至利用COM域进行了串扰，即使来自不同生物合成系统的NRPS之间也是如此。总之，COM域代表了用于生物组合方法的有趣工具，例如，可用于生成创新的天然产物衍生物。

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