Insulin receptor Arg717 and IGF-1 receptor Arg704 play a key role in ligand binding and in receptor activation

The insulin receptor (IR, with its isoforms IR-A and IR-B) and the insulin-like growth factor 1 receptor (IGF-1R) are related tyrosine kinase receptors. Recently, the portfolio of solved hormone-receptor structures has grown extensively thanks to advancements in cryo-electron microscopy. However, the dynamics of how these receptors transition between their inactive and active state are yet to be fully understood. The C-terminal part of the alpha subunit (alpha CT) of the receptors is indispensable for the formation of the hormone-binding site. We mutated the alpha CT residues Arg717 and His710 of IR-A and Arg704 and His697 of IGF-1R. We then measured the saturation binding curves of ligands on the mutated receptors and their ability to become activated. Mutations of Arg704 and His697 to Ala in IGF-1R decreased the binding of IGF-1. Moreover, the number of binding sites for IGF-1 on the His697 IGF-1R mutant was reduced to one-half, demonstrating the presence of two binding sites. Both mutations of Arg717 and His710 to Ala in IR-A inactivated the receptor. We have proved that Arg717 is important for the binding of insulin to its receptor, which suggests that Arg717 is a key residue for the transition to the active conformation.

Automated summary

This study investigates the transition between inactive and active states of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) through mutation of key residues. The results show that these mutations significantly affect the binding and activation abilities of the receptors, providing further insights into the relationship between the structure and function of these receptors.