7942 Evolution of Insulin, Insulin-like Growth Factor and Their Cognate Receptors in Vertebrates, Invertebrates and Viruses

Abstract Disclosure: M. Chrudinova: None. Y.D. Dogru: None. R. Huang: None. R. Reiners: None. P. De Meyts: None. J. DaCosta: None. E. Altindis: None. The insulin/insulin-like growth factor (IGF) signaling system is an evolutionarily conserved system and controls central processes including metabolism, cellular growth, proliferation, and differentiation in vertebrates. On the other hand, invertebrate insulin-like peptides (ILPs) regulate growth, stress responses, longevity and sex-related functions. In addition, we recently showed that six viruses possess viral insulin-like peptides (VILPs) that can bind to the receptors and stimulate post-receptor signaling. The evolution of these hormones and the origin of VILPs are not completely understood. Here, we collected vertebrate and invertebrate insulin, IGF and their cognate receptor sequences to analyze their evolutionary relations. We analyzed 177 vertebrate insulins, 119 vertebrate IGF-1s, 127 vertebrate IGF-2s, 197 invertebrate ILPs and 6 viral insulin/IGF-1 like peptides. We also analyzed 214 insulin receptor (IR), 160 IGF receptor (IGF1R) and 39 invertebrate receptor sequences to identify conservation and the evolutionary trajectory to reveal conserved motifs. Through phylogenetic analyses, we observed a separate branching of invertebrate ILPs and vertebrate insulins, IGF-1s and IGF-2s with notable exceptions including VILPs. IGF-1 and IGF-2 ligands were evolutionally better conserved compared to insulin ligands. Insulin C-peptide which is processed and cleaved was not well conserved compared to the functional A- and B-chain residues. In contrast, C-peptide of IGF-1 that plays an important role in receptor binding was very well conserved. IGF-1 C-domain showed higher variability in IGF1R binding residues compared to the A and B-domains, while residues important for binding of IGF-2 to IGF1R were well conserved. Insulin residues interacting with IR binding Site 1 were more conserved than those interacting with IR binding Site 2, while residues important for insulin dimerization and hexamerization residues are well conserved across species. We also showed that VILPs contain 14 amino acids that are conserved in insulin and IGFs, indicating their functional importance. Phylogenetic relationships of the receptor sequences suggest vertebrate IRs and IGF1Rs evolved from a common ancestor during early vertebrate evolution. Interestingly, receptor subunits revealed a closer relation of amphibian IR α-subunits to Mammalia IR α-subunits than Aves and Reptilians. The conservation rate of receptor residues essential for ligand-receptor interaction revealed that these residues are best conserved in the L1 domain for IR and IGF1R, with a higher rate of variation in other domains for both receptors. Taken together, our study provides a comprehensive analysis of insulin, IGFs, VILPs and their cognate receptors’ evolution, and opens new avenues to better understand the evolution, function, and structure relations of this complex signaling system. Presentation: 6/3/2024