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Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist

Author

Listed:
  • Francois Moreau

    (Joslin Diabetes Center, Harvard Medical School)

  • Nicholas S. Kirk

    (WEHI
    University of Melbourne)

  • Fa Zhang

    (Indiana University)

  • Vasily Gelfanov

    (Indianapolis Research Center)

  • Edward O. List

    (Ohio University)

  • Martina Chrudinová

    (Boston College Biology Department)

  • Hari Venugopal

    (Monash University)

  • Michael C. Lawrence

    (WEHI
    University of Melbourne)

  • Veronica Jimenez

    (Universitat Autonoma de Barcelona
    CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM))

  • Fatima Bosch

    (Universitat Autonoma de Barcelona
    CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM))

  • John J. Kopchick

    (Ohio University)

  • Richard D. DiMarchi

    (Indiana University)

  • Emrah Altindis

    (Boston College Biology Department)

  • C. Ronald Kahn

    (Joslin Diabetes Center, Harvard Medical School)

Abstract

Lymphocystis disease virus-1 (LCDV-1) and several other Iridoviridae encode viral insulin/IGF-1 like peptides (VILPs) with high homology to human insulin and IGFs. Here we show that while single-chain (sc) and double-chain (dc) LCDV1-VILPs have very low affinity for the insulin receptor, scLCDV1-VILP has high affinity for IGF1R where it can antagonize human IGF-1 signaling, without altering insulin signaling. Consequently, scLCDV1-VILP inhibits IGF-1 induced cell proliferation and growth hormone/IGF-1 induced growth of mice in vivo. Cryo-electron microscopy reveals that scLCDV1-VILP engages IGF1R in a unique manner, inducing changes in IGF1R conformation that led to separation, rather than juxtaposition, of the transmembrane segments and hence inactivation of the receptor. Thus, scLCDV1-VILP is a natural peptide with specific antagonist properties on IGF1R signaling and may provide a new tool to guide development of hormonal analogues to treat cancers or metabolic disorders sensitive to IGF-1 without affecting glucose metabolism.

Suggested Citation

  • Francois Moreau & Nicholas S. Kirk & Fa Zhang & Vasily Gelfanov & Edward O. List & Martina Chrudinová & Hari Venugopal & Michael C. Lawrence & Veronica Jimenez & Fatima Bosch & John J. Kopchick & Rich, 2022. "Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34391-6
    DOI: 10.1038/s41467-022-34391-6
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    References listed on IDEAS

    as
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