Insulin receptor /3-subunit

Various hormonal agents (eg, glucocorticoids) lower the affinity of insulin receptors for insulin growth hormone in excess increases this affinity slightly. Aberrant serine and threonine phosphorylation of the insulin receptor subunits or IRS molecules may result in insulin resistance and functional receptor down-regulation. 

Insulin Receptor. Figure 1 Structure and function of the insulin receptor. Binding of insulin to the a-subunits (yellow) leads to activation of the intracellular tyrosine kinase ((3-subunit) by autophosphorylation. The insulin receptor substrates (IRS) bind via a phospho-tyrosine binding domain to phosphorylated tyrosine residues in the juxtamembrane domain of the (3-subunit. The receptor tyrosine kinase then phosphorylates specific tyrosine motifs (YMxM) within the IRS. These tyrosine phosphorylated motifs serve as docking sites for some adaptor proteins with SRC homology 2 (SH2) domains like the regulatory subunit of PI 3-kinase. 

Concanavalin A is a plant lectin from the jack bean (Canavalia ensiformis) which binds with high affinity to mannose residues of glycoproteins. Concanavalin A is known to stimulate the tyrosine kinase activity of the INSR (3-subunit with consecutive activation of kinases downstream the insulin receptor (IRS, PI 3-kinase). It is believed that Concanavalin A stimulates the activation and autophosphorylation of the INSR kinase through aggregation of the receptor, although the precise mechanism of action is unclear. 

The catalytic pi 10 subunit has four isoforms, all of which contain a kinase domain and a Ras interaction site. In addition, the a, (3, and y isoforms possess an interaction site for the p85 subunit. The class I enzymes can be further subdivided class IA enzymes interact through their SH2 domains with phosphotyrosines present on either protein tyrosine kinases or to docking proteins such as insulin-receptor substrates (IRSs GAB-1) or linkers for activation of T cells (LATs in the case of T cells). 

Kirkpatrick RB, Matico RE, McNulty DE, Strickler JE, Rosenberg M 1995 An abundantly secreted glycoprotein from Drosophila melanogaster is related to mammalian secretory proteins produced in rheumatoid tissues and by activated macrophages. Gene 153 147-154 Leconte I, Carpentier JL, Clauser E 1994 The functions of the human insulin receptor are affected in different ways by mutation of each of the four N-glycosylation sites in the fl subunit. J Biol Chem 269 18062-18071... 

Figure 11.2 Structure of the insulin receptor (a). Binding of insulin promotes autophosphorylation of the (3-subunits, where each (3-subunit phosphorylates the other (3-subunit. Phosphate groups are attached to three specific tyrosine residues (tyrosines 1158, 1162 and 1163), as indicated in (b). Activation of the (3-subunit s tyrosine kinase activity in turn results in the phosphorylation of various intracellular (protein) substrates which trigger the mitogen-activated protein kinase and/or the phosphoinositide (PI-3) kinase pathway responsible for inducing insulin s mitogenic and metabolic effects. The underlying molecular events occurring in these pathways are complex (e.g. refer to Combettes-Souverain, M. and Issad, T. 1998. Molecular basis of insulin action. Diabetes and Metabolism, 24, 477-489)...

Insulin binds to the external a subunit of the transmembrane protein insulin receptor. 

The insulin receptor (top) is a dimer with subunits that have activatable tyrosine kinase domains in the interior of the cell (see p. 224). Binding of the hormone increases the tyrosine kinase activity of the receptor, which then phosphorylates itself and other proteins (receptor substrates) at various tyrosine residues. Adaptor proteins, which conduct the signal further, bind to the phosphotyrosine residues. 

The insulin receptor is composed of two heterodimers each heterodimer is composed of an a unit and a P unit. The a unit is extracellular and contains the insulin recognition and binding sites the p unit spans the cellular membrane and contains a tyrosine kinase. Although insulin can bind to a single ap dimer, it binds with higher affinity to the aPaP tetrameric complex. When insulin binds to an a unit, the tyrosine kinase associated with the corresponding p unit is stimulated. Following this, intracellular proteins such as IRS-1 and IRS-2 (IRS=insulin receptor substrate) are phosphorylated by the P subunit tyrosine kinase, and they in turn activate a network of phosphorylations within the receptor cell. 

FIGURE 12-7 Activation of the insulin-receptor Tyr kinase by autophosphorylation. (a) In the inactive form of the Tyr kinase domain (PDB ID 11RK), the activation loop (blue) sits in the active site, and none of the critical Tyr residues (black and red ball-and-stick structures) are phosphorylated. This conformation is stabilized by hydrogen bonding between Tyr1162 and Asp"32, (b) When insulin binds to the a chains of insulin receptors, the Tyr kinase of each /3 subunit of the dimer phosphorylates three Tyr residues (Tyr"58, Tyr"62, and... 

I Insulin binding activates I receptor tyrosine kinase activity in the intracellular domain of the 3 subunit of the insulin receptor. 

Insulin receptor The insulin receptor is synthesized as a single polypeptide that is glycosylated and cleaved into a and 3-sub-units, which are then assembled into a tetramer linked by disulfide bonds (Figure 23.7). A hydrophobic domain in each 3-subunit spans the plasma membrane. The extracellular a-subunit con tains the insulin binding site. The cytosolic domain of the 3-subunit is a tyrosine kinase, which is activated by insulin. 

Signal transduction The binding of insulin to the a-subunits of the insulin receptor induces conformational changes that are transduced to the 3-subunits. This promotes a rapid autophosphorylation of a specific tyrosine residue on each 3-subunit (see Figure 23.7). Autophosphorylation initiates a cascade of cellsignaling responses, including phosphorylation of a family of pro teins called insulin receptor substrate (IRS) proteins. At least four... 

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