Insulin receptors are found on many different cells in the body, including cells in which insulin does not increase glucose uptake. The insulin receptor, which has a molecular weight of approximately 340,000, is a tetramer made up of two α and two β glycoprotein subunits. All these are synthesized on a single mRNA and then proteolytically separated and bound to each other by disulfide bonds.
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| Insulin, IGF-I, and IGF-II receptors. Each hormone binds primarily to its own receptor, but insulin also binds to the IGF-I receptor, and IGF-I and IGF-II bind to all three. The purple boxes are intracellular tyrosine kinase domains. Note the marked similarity between the insulin receptor and the IGF-I receptor; also note the 15 repeat sequences in the extracellular portion of the IGF-II receptor. |
The gene for the insulin receptor has 22 exons and in humans is located on chromosome 19. The α subunits bind insulin and are extracellular, whereas the β subunits span the membrane. The intracellular portions of the β subunits have tyrosine kinase activity. The α and β subunits are both glycosylated, with sugar residues extending into the interstitial fluid.
Binding of insulin triggers the tyrosine kinase activity of the β subunits, producing autophosphorylation of the β subunits on tyrosine residues. The autophosphorylation, which is necessary for insulin to exert its biologic effects, triggers phosphorylation of some cytoplasmic proteins and dephosphorylation of others, mostly on serine and threonine residues. Insulin receptor substrate (IRS- 1) mediates some of the effects in humans but there are other effector systems as well. For example, mice in which the insulin receptor gene is knocked out show marked growth retardation in utero, have abnormalities of the central nervous system (CNS) and skin, and die at birth of respiratory failure, whereas IRS-1 knockouts show only moderate growth retardation in utero, survive, and are insulin-resistant but otherwise nearly normal.
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| Intracellular responses triggered by insulin binding to the insulin receptor. Circles labeled P represent phosphate groups. IRS-1, insulin receptor substrate-1. |
The growth-promoting protein anabolic effects of insulin are mediated via phosphatidylinositol 3-kinase (PI3K), and evidence indicates that in invertebrates, this pathway is involved in the growth of nerve cells and axon guidance in the visual system. It is interesting to compare the insulin receptor with other related receptors. The insulin receptor is very similar to the receptor for IGF-I but different from the receptor for IGF-II. Other receptors for growth factors and receptors for various oncogenes also are tyrosine kinases. However, the amino acid composition of these receptors is quite different. When insulin binds to its receptors, they aggregate in patches and are taken up into the cell by receptor-mediated endocytosis. Eventually, the insulin–receptor complexes enter lysosomes, where the receptors are broken down or recycled. The half-life of the insulin receptor is about 7 h.
Insulin Binding
Both insulin and the IR, consist of two chains. Insulin forms dimers and hexamers, while the receptor forms homodimers on the cell surface. In the past four decades efforts have focused on understanding how many copies of the insulin monomer are required to activate the homodimeric IR. Although the IR dimer can potentially bind two insulin molecules, negative cooperativity in the IR results in one insulin monomer binding to the dimeric receptor with high affinity, while any additional insulin binding is of lower affinity.
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| Complex of insulin and a truncated version of the insulin receptor shown in ribbon representation (PDB ID 5kqv, Menting et al., 2013). The L1, CR, L2, FN III-1 and α-CT are color coded to display their locations in this complex. The insulin molecule is colored in blue and green and its surface is drawn for easy identification. A second chain of the truncated IR protein is shown in ribbon representation and colored grey. |
Monomeric insulin occupies one of the insulin binding sites (near domains L1, Fn III- 1, and α-CT). Since the IR structure is large and complex, a truncated, yet functional, version of the receptor was designed for use in mechanistic studies. The truncated form of IR includes only those domains that participate in hormone binding (i.e., L1, CR, L2, Fn III-1, and α-CT). Structural studies of complexes of this truncated receptor with insulin revealed how insulin sits atop the L1 domain and interacts with the α-CT helix. Complex formation involves movement of the C-terminal strand of the insulin B chain to expose amino acids critical for IR binding and to accommodate α-CT helix binding.
Although crystal structures of the soluble IR ectodomain bound to insulin show both insulin binding sites occupied, recent cryo-electron microscopy studies reveal that dimers of full length IRs can bind either one or two insulin molecules. Conformational changes induced in the IR dimer following insulin binding are thought to propagate across the cell membrane and activate the intracellular Tyr-K domains leading to trans-autophosphorylation of the both IRs and initiation of the signaling cascade. The precise order of these conformational changes in the various domains of IR and molecular details of this process remain active areas of investigation.
References
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