Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist
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.
Moreau, Francois; Kirk, Nicholas S.; Zhang, Fa; Gelfanov, Vasily; List, Edward O.; Chrudinová, Martina; Venugopal, Hari; Lawrence, Michael C.; Jimenez, Veronica; Bosch, Fatima; Kopchick, John J.; DiMarchi, Richard D.; Altindis, Emrah; and Ronald Kahn, C., "Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist" (2022). Edison Biotechnology Institute Open Access Publications. 1.