Poster Presentation The 48th Lorne Conference on Protein Structure and Function 2023

CryoEM studies of viral IGF-like ligands of the human IGF receptor (#229)

Nicholas S Kirk 1
  1. WEHI, Parkville, VIC, Australia

Iridoviruses such as lymphocystis disease virus-1 (LCDV-1) and mandarinfish ranavirus (MFRV) encode viral insulin-like growth factor-like peptides (VILPs) with high homology to human insulin and IGF (Altindis, 2018). These iridoviruses infect commercial food and ornamental fish that come into regular contact with humans and their DNA has been observed in human faecal and blood samples (Norman, 2015; Dinakaran, 2014). Due to their similarity to the human homologues, VILPs therefore represent potential immunogenic factors for the development of diabetes and other auto-immune conditions. They are also unusual examples of insulin-like peptides in many regards.

Here I will present the first cryoEM structures of VILPs in complex with the human IGF1-receptor (IGF1R). The first peptide, scLCDV1-VILP, demonstrates a unique two-ligand bound, signalling-inhibited structure and allows us to determine the molecular mechanism for IGF1R antagonism by IGF-like peptides. scLCDV1-VILP is also shown to inhibit IGF1-induced cell proliferation and growth in vivo in mice and produce a unique phosphorylation signal in human cells (Moreau and Kirk, 2022). The 3-angstrom structure of the most potent VILP agonist found to-date, scMFRV-VILP, bound to the human IGF1 receptor is also shown, highlighting the key motifs that differentiate viral agonists and antagonists of IGF1R. Biochemical studies of both VILPs on human cells further elucidate the function and dynamics of IGF and insulin signalling in humans and represent useful chemical matter to help design better therapeutics for both diabetes and cancer. Together, these data represent the first thorough assessment of VILPs in the context of mammals and demonstrate their utility in the study of insulin and IGF signalling and potential impact on auto-immunity.

  1. Altindis, E. et al. Viral insulin-like peptides activate human insulin and IGF-1 receptor signaling: A paradigm shift for host-microbe interactions. Proc Natl Acad Sci U S A 115, 2461-2466, doi:10.1073/pnas.1721117115 (2018).
  2. Norman, J. M. et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 160, 447-460, doi:10.1016/j.cell.2015.01.002 (2015).
  3. Dinakaran, V. et al. Elevated levels of circulating DNA in cardiovascular disease patients: metagenomic profiling of microbiome in the circulation. PLoS One 9, e105221, doi:10.1371/journal.pone.0105221 (2014).
  4. Moreau, F and Kirk, N. S. et al. Unique interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist. Nat. Comms. accepted manuscript (2022).