Steric complementarity directs sequence promiscuous leader binding in RiPP biosynthesis
Abstract
Enzymes that generate ribosomally synthesized and posttranslationally modified peptide (RiPP) natural products have garnered significant interest, given their ability to produce large libraries of chemically diverse scaffolds. Such RiPP biosynthetic enzymes are predicted to bind their corresponding peptide substrates through sequence-specific recognition of the leader sequence, which is removed after the installation of posttranslational modifications on the core sequence. The conservation of the leader sequence within a given RiPP class, in otherwise disparate precursor peptides, further supports the notion that strict sequence specificity is necessary for leader peptide engagement. Here, we demonstrate that leader binding by a biosynthetic enzyme in the lasso peptide class of RiPPs is directed by a minimal number of hydrophobic interactions. Biochemical and structural data illustrate how a single leader-binding domain can engage sequence-divergent leader peptides using a conserved motif that facilitates hydrophobic packing. We report the presence of this simple motif in noncognate peptides results in low micromolar affinity binding by binding domains from several different lasso biosynthetic systems. We also demonstrate that these observations likely extend to other RiPP biosynthetic classes. The portability of the binding motif opens avenues for the engineering of semisynthetic hybrid RiPP products.
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- National Institutes of Health (NIH)
- OSTI Identifier:
- 1578220
- Grant/Contract Number:
- GM079038
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Volume: 116; Journal Issue: 48; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; biochemistry; RiPPs; biosynthesis
Citation Formats
Chekan, Jonathan R., Ongpipattanakul, Chayanid, and Nair, Satish K. Steric complementarity directs sequence promiscuous leader binding in RiPP biosynthesis. United States: N. p., 2019.
Web. doi:10.1073/pnas.1908364116.
Chekan, Jonathan R., Ongpipattanakul, Chayanid, & Nair, Satish K. Steric complementarity directs sequence promiscuous leader binding in RiPP biosynthesis. United States. https://doi.org/10.1073/pnas.1908364116
Chekan, Jonathan R., Ongpipattanakul, Chayanid, and Nair, Satish K. Tue .
"Steric complementarity directs sequence promiscuous leader binding in RiPP biosynthesis". United States. https://doi.org/10.1073/pnas.1908364116. https://www.osti.gov/servlets/purl/1578220.
@article{osti_1578220,
title = {Steric complementarity directs sequence promiscuous leader binding in RiPP biosynthesis},
author = {Chekan, Jonathan R. and Ongpipattanakul, Chayanid and Nair, Satish K.},
abstractNote = {Enzymes that generate ribosomally synthesized and posttranslationally modified peptide (RiPP) natural products have garnered significant interest, given their ability to produce large libraries of chemically diverse scaffolds. Such RiPP biosynthetic enzymes are predicted to bind their corresponding peptide substrates through sequence-specific recognition of the leader sequence, which is removed after the installation of posttranslational modifications on the core sequence. The conservation of the leader sequence within a given RiPP class, in otherwise disparate precursor peptides, further supports the notion that strict sequence specificity is necessary for leader peptide engagement. Here, we demonstrate that leader binding by a biosynthetic enzyme in the lasso peptide class of RiPPs is directed by a minimal number of hydrophobic interactions. Biochemical and structural data illustrate how a single leader-binding domain can engage sequence-divergent leader peptides using a conserved motif that facilitates hydrophobic packing. We report the presence of this simple motif in noncognate peptides results in low micromolar affinity binding by binding domains from several different lasso biosynthetic systems. We also demonstrate that these observations likely extend to other RiPP biosynthetic classes. The portability of the binding motif opens avenues for the engineering of semisynthetic hybrid RiPP products.},
doi = {10.1073/pnas.1908364116},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 48,
volume = 116,
place = {United States},
year = {Tue Nov 12 00:00:00 EST 2019},
month = {Tue Nov 12 00:00:00 EST 2019}
}
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