Abstract
Ribosomally synthesized and post-translationally modified peptides (RiPPs) are natural products with diverse structures and functions. Here, we report the discovery of a family of RiPPs whose biosynthetic gene clusters are widespread in the Bacillota genomes and often co-localize with those of lasso peptides, another distinct family of RiPPs. The synthesis of both kinds of RiPPs relies on specific interactions between small adapter protein domains known as RiPP recognition elements (RREs) with their precursor peptides. As these latter share a conserved RRE-binding motif, conflicts between the two biosynthetic pathways may emerge. Through biochemical and structural studies, we reveal how the two RiPP biosynthetic systems evolved to discriminate between their cognate precursors and leader peptidases, allowing them to coexist within a single host. Thus, our study provides insights into the evolutionary diversification of RiPP families.
Acknowledgements
We thank Dr. Dmitrii Travin (University of Illinois in Chicago, USA), Dr. Yanyan Li (Muséum national d’Histoire naturelle, France), and Françoise Jacob Dubuisson (Institute Pasteur de Lille, France) for the fruitful discussion and valuable insights. We thank MetaboHub-MetaToul (Metabolomics and Fluxomics facilities, Toulouse, France (http://www.mth-metatoul.fr), part of the French National Infrastructure for Metabolomics and Fluxomics (http://www.metabohub.fr) funded by a grant from the Agence Nationale de la Recherche Scientifique (MetaboHUB-ANR-11-INBS-0010 and the Moscow State University Development Program APG 5.13 for access to the mass spectrometry facility. We are grateful to the scientists at the SPring-8 BL32XU and Photon Factory BL-5A for collecting the diffraction data. S.D. discloses support for the research of this work from INRAE EXPLOR’AE program, a part of the France 2030 initiative, grant ANR-24-RRII-0003; a fellowship of the Collège de France and the INRAE. G.L. discloses support for the research and publication of this work from INRAE EXPLOR’AE program, a part of the France 2030 initiative, grant ANR-24-RRII-0003, and ANR-25-CE44-1111. A.G. discloses support for the research of this work from the Russian Science Foundation grant RSF22-24-00684 to Julia Andreeva. K.S. discloses support from the Russian Science Foundation grant RSF 24-140081. A.P. discloses support for the research and publication of this work from the RIKEN Junior Research Associate Program. Y.I.W discloses support for the research of this work from the Intramural Research Program of the National Institutes of Health (NIH). D.B., M.S. and A.W. declare no relevant funding. The contributions of the NIH author(s) are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Source data
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Popov, A., Bikmetov, D., Grigoreva, A. et al. RiPP recognition elements evolved to prevent pathway interference through leader peptide discrimination. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73250-6
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41467-026-73250-6
