Many ribosomally synthesized and posttranslationally modified peptide classes (RiPPs) are reliant on a domain called the RiPP recognition element (RRE). The RRE binds specifically to a precursor peptide and directs the posttranslational modification enzymes to their substrates. Given its prevalence across various types of RiPP biosynthetic gene clusters (BGCs), the RRE could theoretically be used as a bioinformatic handle to identify novel classes of RiPPs. In addition, due to the high affinity and specificity of most RRE-precursor peptide complexes, a thorough understanding of the RRE domain could be exploited for biotechnological applications. However, sequence divergence of RREs across RiPP classes has precluded automated identification based solely on sequence similarity. Here, we introduce RRE-Finder, a new tool for identifying RRE domains with high sensitivity. RRE-Finder can be used in precision mode to confidently identify RREs in a class-specific manner or in exploratory mode to assist in the discovery of novel RiPP classes. RRE-Finder operating in precision mode on the UniProtKB protein database retrieved ∼25,000 high-confidence RREs spanning all characterized RRE-dependent RiPP classes, as well as several yet-uncharacterized RiPP classes that require future experimental confirmation. Finally, RRE-Finder was used in precision mode to explore a possible evolutionary origin of the RRE domain. The results suggest RREs originated from a co-opted DNA-binding transcriptional regulator domain. Altogether, RRE-Finder provides a powerful new method to probe RiPP biosynthetic diversity and delivers a rich data set of RRE sequences that will provide a foundation for deeper biochemical studies into this intriguing and versatile protein domain.

中文翻译：

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RRE-Finder：一种用于类无关 RiPP 发现的基因组挖掘工具。

许多核糖体合成和翻译后修饰的肽类 (RiPP) 依赖于称为 RiPP 识别元件 (RRE) 的域。RRE 与前体肽特异性结合，并将翻译后修饰酶引导至其底物。鉴于其在各种类型的 RiPP 生物合成基因簇 (BGC) 中的普遍性，理论上 RRE 可以用作识别新型 RiPP 的生物信息学句柄。此外，由于大多数 RRE 前体肽复合物的高亲和力和特异性，对 RRE 结构域的透彻了解可用于生物技术应用。然而，RREs 跨 RiPP 类的序列差异已经排除了仅基于序列相似性的自动识别。在这里，我们介绍 RRE-Finder，一种用于以高灵敏度识别 RRE 域的新工具。RRE-Finder 可用于精确模式，以特定于类的方式或探索性模式自信地识别 RRE，以帮助发现新的 RiPP 类。在 UniProtKB 蛋白质数据库上以精确模式运行的 RRE-Finder 检索到了大约 25,000 个高置信度 RRE，涵盖所有表征的 RRE 依赖性 RiPP 类别，以及几个需要未来实验确认的尚未表征的 RiPP 类别。最后，在精确模式下使用 RRE-Finder 来探索 RRE 域的可能进化起源。结果表明 RREs 起源于一个共同选择的 DNA 结合转录调节域。共，