Title:
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Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist
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Author:
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Moreau, Francois; Kirk, Nicholas S.; Zhang, Fa; Gelfanov, Vasily; List, Edward O.; Chrudinová, Martina; Venugopal, Hari; Lawrence, Michael C.; Jimenez, Veronica; Bosch i Tubert, Fàtima; Kopchick, John J.; DiMarchi, Richard D.; Altindis, Emrah; Ronald Kahn, C.
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Abstract:
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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. |
Subject(s):
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-Cryoelectron microscopy -Cell growth -Growth factor signalling -Peptides |
Rights:
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open access
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https://creativecommons.org/licenses/by/4.0/ |
Document type:
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Article |
Published by:
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Share:
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Uri:
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https://ddd.uab.cat/record/268515
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