Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist
Moreau, Francois ![Identificador ORCID](/img/uab/orcid.ico)
(Harvard Medical School. Joslin Diabetes Center)
Kirk, Nicholas S. ![Identificador ORCID](/img/uab/orcid.ico)
(University of Melbourne. Department of Medical Biology)
Zhang, Fa (Indiana University. Department of Chemistry)
Gelfanov, Vasily (Indianapolis Research Center)
List, Edward O. (Ohio University. Edison Biotechnology Institute and Heritage College of Osteopathic Medicine)
Chrudinová, Martina (Boston College Biology Department)
Venugopal, Hari (Monash University. Ramaciotti Centre for Cryo-Electron Microscopy)
Lawrence, Michael C.
(University of Melbourne. Department of Medical Biology)
Jimenez, Veronica
(Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i de Teràpia Gènica (CBATEG))
Bosch i Tubert, Fàtima
(Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i de Teràpia Gènica (CBATEG))
Kopchick, John J.
(Ohio University. Edison Biotechnology Institute and Heritage College of Osteopathic Medicine)
DiMarchi, Richard D.
(Indiana University. Department of Chemistry)
Altindis, Emrah
(Boston College Biology Department)
Ronald Kahn, C.
(Harvard Medical School. Joslin Diabetes Center)
Fecha: |
2022 |
Resumen: |
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. The authors previously identified a family of viral insulin-like peptides (VILPs) with high homology to human insulin/IGF−1. Here, they report that one of these VILPs exhibits antagonist properties associated with a unique conformation of the IGF1R. |
Derechos: |
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Lengua: |
Anglès |
Documento: |
Article ; recerca ; Versió publicada |
Materia: |
Cryoelectron microscopy ;
Cell growth ;
Growth factor signalling ;
Peptides |
Publicado en: |
Nature communications, Vol. 13 (november 2022) , ISSN 2041-1723 |
DOI: 10.1038/s41467-022-34391-6
PMID: 36335114
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Registro creado el 2022-11-17, última modificación el 2023-03-20