Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist
- Author(s)
- Moreau, F; Kirk, NS; Zhang, F; Gelfanov, V; List, EO; Chrudinova, M; Venugopal, H; Lawrence, MC; Jimenez, V; Bosch, F; Kopchick, JJ; DiMarchi, RD; Altindis, E; Ronald Kahn, C;
- Details
- Publication Year 2022-11-05,Volume 13,Issue #1,Page 6700
- Journal Title
- Nature Communications
- 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.
- Publisher
- NPG
- Keywords
- Humans; Mice; Animals; *Receptor, IGF Type 1/metabolism; *Insulin-Like Growth Factor I/metabolism; Insulin/metabolism; Cryoelectron Microscopy; Peptides/pharmacology
- Research Division(s)
- Structural Biology
- PubMed ID
- 36335114
- Publisher's Version
- https://doi.org/10.1038/s41467-022-34391-6
- Open Access at Publisher's Site
https://doi.org/10.1038/s41467-022-34391-6- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2022-12-13 03:12:57
Last Modified: 2022-12-14 11:45:20