Insulin Receptor Complex and Signaling by Insulin

Publisher Summary This chapter briefly explores the nature of the insulin receptor (IR), its interaction with insulin, and its signaling to a major metabolic target, glucose transport. IR is a glycosylated, disulfide-linked homodimer with each monomer being made up of an α chain that is entirely extracellular and a β chain that spans the cell membrane once. The α chain contains the insulin binding determinants of the receptor, while the intracellular portion of the β chain includes a protein tyrosine kinase domain and domains involved in binding signal transduction proteins. The IR ectodomain has a single disulfide bond linking the α and β chains, joining residues 647 and 872 (exon 11 plus form), and at least two disulfides symmetrically linking the α chains of the dimer. Binding of insulin to the IR is thought to be accompanied by a conformational change at each end of the insulin B chain, leading to exposure of hydrophobic residues from the core and formation of one binding site, the classical binding site. Thus, movement of the C-terminal 8-10 residues would expose key residues, IleA2 and ValA3, while residues IleA10, LeuA13, and LeuB6 are exposed by changes of the N-terminal 8 residues of the B chain. The classical binding site of insulin is bound to a conserved hydrophobic patch on the surface of the L1 domain of the IR in such a way that the second site corresponding to the hexamer face of the insulin molecule is available for further interaction with the receptor.