Journal article
Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist
F Moreau, NS Kirk, F Zhang, V Gelfanov, EO List, M Chrudinová, H Venugopal, MC Lawrence, V Jimenez, F Bosch, JJ Kopchick, RD DiMarchi, E Altindis, C Ronald Kahn
Nature Communications | NATURE PORTFOLIO | Published : 2022
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 j..
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Awarded by National Institutes of Health
Funding Acknowledgements
This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award number R01DK031036 (to C.R.K.) and K01DK117967 (to E.A.). We thank Ms Mai Margetts and Dr Yibin Xu (WEHI, Parkville) for the provision of an aliquot of IGF1Rzip for use in these studies and Prof. Ken Siddle (University of Cambridge) for providing MCL's laboratory with the hybridomas used to expressmAb 26-60 and mAb 83-7. Stable cell lines expressing receptor ectodomains were obtained from CSIRO (Parkville, Australia) by WEHI under a Technology Transfer Agreement. WEHI receives Victorian State Government Operational Infrastructure Support and funding from the Australian NHMRC Independent Research Institutes Infrastructure Support Scheme. The authors acknowledge the use of instruments and assistance at the Monash Ramaciotti Centre for Cryo-Electron Microscopy, a Node of Microscopy Australia and the use of equipment funded by the Australian Research Council grant LE120100090.