Hidden Diversity in Myxobacterial Lasso Peptides: An Atypical RiPP Recognition Element and Host-Mediated Loss of the Lasso Tail
Abstract
Cystonodins and soranginodins are the first lasso peptides identified from the phylum Myxococcota and reveal unexpected diversity in lasso peptide biosynthesis. Whereas the soranginodin pathways combine canonical fused RREproteases with precursor peptides retaining the YxxP motif, the cystonodin pathway contains McyB, a functional fused RRE-protease with a shortened N-terminal domain that adopts an atypical RRE architecture, retaining the characteristic β-sheets but lacking much of the canonical αhelical region. A targeted bioinformatic survey of apparent standalone lasso proteases identified 52 cryptic RREprotease fusions; subsequent structural analysis revealed both typical and atypical fused RREs architectures, exposing a blind spot in RRE detection and BGC annotation. We additionally identified several C-terminally truncated cystonodin congeners, including an unprecedented tail-less variant consisting solely of the macrolactam ring. In vitro reconstitution and biochemical characterization implicate endogenous host protease(s) in these cleavage events. Together, these findings highlight the value of integrating structural information into genome-mining workflows and expose host-dependent remodelling as a potential pitfall of
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BibTeX
@misc{sikandar2026hidden,
title = {{Hidden Diversity in Myxobacterial Lasso Peptides: An Atypical RiPP Recognition Element and Host-Mediated Loss of the Lasso Tail}},
author = {Asfandyar Sikandar and Haowen Zhao and Guangyi Chen and Lucile Moynié and James H. Naismith and Olga V. Kalinina and Rolf Müller},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15009246/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009246/v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Hidden Diversity in Myxobacterial Lasso Peptides: An Atypical RiPP Recognition Element and Host-Mediated Loss of the Lasso Tail
AU - Asfandyar Sikandar
AU - Haowen Zhao
AU - Guangyi Chen
AU - Lucile Moynié
AU - James H. Naismith
AU - Olga V. Kalinina
AU - Rolf Müller
PY - 2026
DA - 2026/09/22
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009246/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009246/v1
AB - Cystonodins and soranginodins are the first lasso peptides identified from the phylum Myxococcota and reveal unexpected diversity in lasso peptide biosynthesis. Whereas the soranginodin pathways combine canonical fused RREproteases with precursor peptides retaining the YxxP motif, the cystonodin pathway contains McyB, a functional fused RRE-protease with a shortened N-terminal domain that adopts an atypical RRE architecture, retaining the characteristic β-sheets but lacking much of the canonical αhelical region. A targeted bioinformatic survey of apparent standalone lasso proteases identified 52 cryptic RREprotease fusions; subsequent structural analysis revealed both typical and atypical fused RREs architectures, exposing a blind spot in RRE detection and BGC annotation. We additionally identified several C-terminally truncated cystonodin congeners, including an unprecedented tail-less variant consisting solely of the macrolactam ring. In vitro reconstitution and biochemical characterization implicate endogenous host protease(s) in these cleavage events. Together, these findings highlight the value of integrating structural information into genome-mining workflows and expose host-dependent remodelling as a potential pitfall of
ER -