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Mechanistic insights into lanthipeptide modification by a distinct subclass of LanKC enzyme that forms dimers

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  • Yifan Li

    (National University of Singapore)

  • Kai Shao

    (National University of Singapore)

  • Zhaoxing Li

    (School of Pharmacy, China Pharmaceutical University)

  • Kongfu Zhu

    (National University of Singapore)

  • Bee Koon Gan

    (National University of Singapore)

  • Jian Shi

    (National University of Singapore)

  • Yibei Xiao

    (School of Pharmacy, China Pharmaceutical University)

  • Min Luo

    (National University of Singapore
    National University of Singapore)

Abstract

Naturally occurring lanthipeptides, peptides post-translationally modified by various enzymes, hold significant promise as antibiotics. Despite extensive biochemical and structural studies, the events preceding peptide modification remain poorly understood. Here, we identify a distinct subclass of lanthionine synthetase KC (LanKC) enzymes with distinct structural and functional characteristics. We show that PneKC, a member of this subclass, forms a dimer and possesses GTPase activity. Through three cryo-EM structures of PneKC, we illustrate different stages of peptide PneA binding, from initial recognition to full binding. Our structures show the kinase domain complexed with the PneA core peptide and GTPγS, a phosphate-bound lyase domain, and an unconventional cyclase domain. The leader peptide of PneA interact with a gate loop, transitioning from an extended to a helical conformation. We identify a dimerization hot spot and propose a “negative cooperativity” mechanism toggling the enzyme between tense and relaxed conformation. Additionally, we identify an important salt bridge in the cyclase domain, differing from those in in conventional cyclase domains. These residues are highly conserved in the LanKC subclass and are part of two signature motifs. These results unveil potential differences in lanthipeptide modification enzymes assembly and deepen our understanding of allostery in these multifunctional enzymes.

Suggested Citation

  • Yifan Li & Kai Shao & Zhaoxing Li & Kongfu Zhu & Bee Koon Gan & Jian Shi & Yibei Xiao & Min Luo, 2024. "Mechanistic insights into lanthipeptide modification by a distinct subclass of LanKC enzyme that forms dimers," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51600-6
    DOI: 10.1038/s41467-024-51600-6
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    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. Manuel A. Ortega & Yue Hao & Qi Zhang & Mark C. Walker & Wilfred A. van der Donk & Satish K. Nair, 2015. "Structure and mechanism of the tRNA-dependent lantibiotic dehydratase NisB," Nature, Nature, vol. 517(7535), pages 509-512, January.
    3. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
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