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The proline-rich antimicrobial peptide Api137 disrupts large ribosomal subunit assembly and induces misfolding

Author

Listed:
  • Simon Malte Lauer

    (corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin
    10099)

  • Jakob Gasse

    (Universität Leipzig
    Universität Leipzig)

  • Andor Krizsan

    (Universität Leipzig
    Universität Leipzig)

  • Maren Reepmeyer

    (Universität Leipzig
    Universität Leipzig)

  • Thiemo Sprink

    (Charité - Universitätsmedizin Berlin
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association)

  • Rainer Nikolay

    (corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin
    Max Planck Institute for Molecular Genetics)

  • Christian M. T. Spahn

    (corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin)

  • Ralf Hoffmann

    (Universität Leipzig
    Universität Leipzig)

Abstract

The proline-rich antimicrobial designer peptide Api137 inhibits protein expression in bacteria by binding simultaneously to the ribosomal polypeptide exit tunnel and the release factor (RF), depleting the cellular RF pool and leading to ribosomal arrest at stop codons. This study investigates the additional effect of Api137 on the assembly of ribosomes using an Escherichia coli reporter strain expressing one ribosomal protein per 30S and 50S subunit tagged with mCherry and EGFP, respectively. Separation of cellular extracts derived from cells exposed to Api137 in a sucrose gradient reveals elevated levels of partially assembled and not fully matured precursors of the 50S subunit (pre-50S). High-resolution structures obtained by cryogenic electron microscopy demonstrate that a large proportion of pre-50S states are missing up to five proteins (uL22, bL32, uL29, bL23, and uL16) and have misfolded helices in 23S rRNA domain IV. These data suggest a second mechanism for Api137, wherein it disrupts 50S subunit assembly by inducing the formation of misfolded precursor particles potentially incapable of evolving into active ribosomes, suggesting a bactericidal mechanism.

Suggested Citation

  • Simon Malte Lauer & Jakob Gasse & Andor Krizsan & Maren Reepmeyer & Thiemo Sprink & Rainer Nikolay & Christian M. T. Spahn & Ralf Hoffmann, 2025. "The proline-rich antimicrobial peptide Api137 disrupts large ribosomal subunit assembly and induces misfolding," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-55836-8
    DOI: 10.1038/s41467-025-55836-8
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    References listed on IDEAS

    as
    1. Kai Sheng & Ning Li & Jessica N. Rabuck-Gibbons & Xiyu Dong & Dmitry Lyumkis & James R. Williamson, 2023. "Assembly landscape for the bacterial large ribosomal subunit," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Simon M. Lauer & Maren Reepmeyer & Ole Berendes & Dorota Klepacki & Jakob Gasse & Sara Gabrielli & Helmut Grubmüller & Lars V. Bock & Andor Krizsan & Rainer Nikolay & Christian M. T. Spahn & Ralf Hoff, 2024. "Multimodal binding and inhibition of bacterial ribosomes by the antimicrobial peptides Api137 and Api88," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Bo Qin & Simon M. Lauer & Annika Balke & Carlos H. Vieira-Vieira & Jörg Bürger & Thorsten Mielke & Matthias Selbach & Patrick Scheerer & Christian M. T. Spahn & Rainer Nikolay, 2023. "Cryo-EM captures early ribosome assembly in action," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
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