Molecular mechanisms underlying insulin-like growth factor action: How mutations in the GH: IGF axis lead to short stature.

Insulin-like growth factors (IGFs) act via the Type 1 IGF receptor (IGF-1R) to promote growth and development. Recent structural and site-directed mutagenesis studies have provided detailed insight into the mechanism of interaction between the IGFs and the IGF-IR. Studies of the insulin: insulin receptor interaction have provided important additional understanding of the mechanisms underlying the IGF:IGF-1R interaction. The recent crystal structure of the insulin receptor ectodomain showed a folded over conformation accommodating two potential ligand binding pockets. The ligand interacts with the receptor at two different sites within a binding pocket to achieve high affinity binding and activation of the receptor. In this review the effect of mutations in the human IGF1 and IGF-1R genes so for reported are explained in terms of the effect on ligand binding and receptor activation. The severity of patient phenotype can generally be correlated to the effect of the mutation on protein structure and function.