How Insulin-Like Growth Factor Hormones, IGF1 And IGF2, Engage their Cognate Receptor

Abstract

The type 1 insulin-like growth factor receptor (IGF1R), a trans-membrane glycoprotein, is activated by binding of its cognate growth hormones, IGF1 and IGF2. The IGF family was suggested to play a key role in cancer development and progression, thereby making it a potential target for anti-cancer therapeutic efforts. However, the molecular mechanisms underlying hormone-receptor interactions are unclear, as are the molecular bases for differing affinity of each hormone, due in part to the fact that there have been so far no detailed structural models of IGFs-bound-IGF1R to test. Constructed using a homology model of the IGF1R ectodomain, and the NMR structures of IGF1/2, with the help of an MD-assisted Monte-Carlo approach, we present the first experimentally consistent all-atom structural models of IGF1/IGF1R and IGF2/IGF1R complexes. Our models are notable because each hormone remains stably bound in independent 36-ns long explicit-solvent molecular dynamics (MD) simulations. The asymmetric structural relaxation of the apo-IGF1R homology model in a 30-ns MD equilibration facilitated the computational docking of each hormone. Our predicted complexes are significant because we observe simultaneous contacts of each hormone with the site 1 (formed by L1 and CR), and site 2 (formed by L2, and the fibronectin domains), of the receptor, suggesting cross-linking of receptor subunits. Interestingly, we observe differences in recognition of each hormone by IGF1R, because IGF1 interacts relatively strongly with L1 and CR (IGF1R), whereas IGF2 has stronger interactions with L2 and the fibronectin domains. Our simulations also provide direct evidence in favor of previously suggested electrostatic complementarity between the C-domains of IGF1/2 and the CR-domain of the receptor. Additionally, we provide detailed hormone-receptor contacts that are consistent with earlier mutagenesis studies.