The insulin-binding domain of insulin receptor is encoded by exon 2 and exon 3.
Insulin receptors are disulfide-linked oligotetramers composed of two heterodimers each containing a 130-kDa alpha subunit and a 90-kDa beta subunit. Insulin binds to the extracellular alpha subunit, and in the process stimulates the autophosphorylation of the beta subunit and the expression of tyrosine kinase activity. Studies combining the use of photoaffinity labeling and immunoprecipitation with anti-peptide antibody have directly demonstrated that the cysteine-rich domain, encoded by exon 3, in the alpha subunit is part of the insulin-binding site of the receptor. Experiments with chimeric insulin receptors and chimeric insulin-like growth factor I receptors have confirmed that the cysteine-rich domain constitutes a part of the insulin-binding site. In addition, results from these experiments suggest that the N-terminal sequence, encoded by exon 2, in the alpha subunit also participates in insulin binding. In this review it is proposed that, assuming two insulin-binding sites per each holoreceptor oligotetramer, each insulin-binding domain may contain respectively two sub-domains for hydrophobic and charge contact with insulin, and that high-affinity binding would require the interaction of both subunits with the possibility of each subunit reciprocally contributing one of the sub-domains.