RRE-Finder: a Genome-Mining Tool for Class-Independent RiPP Discovery

ABSTRACT 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 pr...

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Autores principales:	Alexander M. Kloosterman, Kyle E. Shelton, Gilles P. van Wezel, Marnix H. Medema, Douglas A. Mitchell
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	RRE RiPPs bioinformatics genome mining natural products secondary metabolism Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ce25faef136a41aa9e3347852a036493
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spelling	oai:doaj.org-article:ce25faef136a41aa9e3347852a0364932021-12-02T19:46:19ZRRE-Finder: a Genome-Mining Tool for Class-Independent RiPP Discovery10.1128/mSystems.00267-202379-5077https://doaj.org/article/ce25faef136a41aa9e3347852a0364932020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00267-20https://doaj.org/toc/2379-5077ABSTRACT 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. IMPORTANCE Bioinformatics-powered discovery of novel ribosomal natural products (RiPPs) has historically been hindered by the lack of a common genetic feature across RiPP classes. Herein, we introduce RRE-Finder, a method for identifying RRE domains, which are present in a majority of prokaryotic RiPP biosynthetic gene clusters (BGCs). RRE-Finder identifies RRE domains 3,000 times faster than current methods, which rely on time-consuming secondary structure prediction. Depending on user goals, RRE-Finder can operate in precision mode to accurately identify RREs present in known RiPP classes or in exploratory mode to assist with novel RiPP discovery. Employing RRE-Finder on the UniProtKB database revealed several high-confidence RREs in novel RiPP-like clusters, suggesting that many new RiPP classes remain to be discovered.Alexander M. KloostermanKyle E. SheltonGilles P. van WezelMarnix H. MedemaDouglas A. MitchellAmerican Society for MicrobiologyarticleRRERiPPsbioinformaticsgenome miningnatural productssecondary metabolismMicrobiologyQR1-502ENmSystems, Vol 5, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	RRE RiPPs bioinformatics genome mining natural products secondary metabolism Microbiology QR1-502
spellingShingle	RRE RiPPs bioinformatics genome mining natural products secondary metabolism Microbiology QR1-502 Alexander M. Kloosterman Kyle E. Shelton Gilles P. van Wezel Marnix H. Medema Douglas A. Mitchell RRE-Finder: a Genome-Mining Tool for Class-Independent RiPP Discovery
description	ABSTRACT 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. IMPORTANCE Bioinformatics-powered discovery of novel ribosomal natural products (RiPPs) has historically been hindered by the lack of a common genetic feature across RiPP classes. Herein, we introduce RRE-Finder, a method for identifying RRE domains, which are present in a majority of prokaryotic RiPP biosynthetic gene clusters (BGCs). RRE-Finder identifies RRE domains 3,000 times faster than current methods, which rely on time-consuming secondary structure prediction. Depending on user goals, RRE-Finder can operate in precision mode to accurately identify RREs present in known RiPP classes or in exploratory mode to assist with novel RiPP discovery. Employing RRE-Finder on the UniProtKB database revealed several high-confidence RREs in novel RiPP-like clusters, suggesting that many new RiPP classes remain to be discovered.
format	article
author	Alexander M. Kloosterman Kyle E. Shelton Gilles P. van Wezel Marnix H. Medema Douglas A. Mitchell
author_facet	Alexander M. Kloosterman Kyle E. Shelton Gilles P. van Wezel Marnix H. Medema Douglas A. Mitchell
author_sort	Alexander M. Kloosterman
title	RRE-Finder: a Genome-Mining Tool for Class-Independent RiPP Discovery
title_short	RRE-Finder: a Genome-Mining Tool for Class-Independent RiPP Discovery
title_full	RRE-Finder: a Genome-Mining Tool for Class-Independent RiPP Discovery
title_fullStr	RRE-Finder: a Genome-Mining Tool for Class-Independent RiPP Discovery
title_full_unstemmed	RRE-Finder: a Genome-Mining Tool for Class-Independent RiPP Discovery
title_sort	rre-finder: a genome-mining tool for class-independent ripp discovery
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/ce25faef136a41aa9e3347852a036493
work_keys_str_mv	AT alexandermkloosterman rrefinderagenomeminingtoolforclassindependentrippdiscovery AT kyleeshelton rrefinderagenomeminingtoolforclassindependentrippdiscovery AT gillespvanwezel rrefinderagenomeminingtoolforclassindependentrippdiscovery AT marnixhmedema rrefinderagenomeminingtoolforclassindependentrippdiscovery AT douglasamitchell rrefinderagenomeminingtoolforclassindependentrippdiscovery
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RRE-Finder: a Genome-Mining Tool for Class-Independent RiPP Discovery

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