Insulin binding

The insulin-binding domain of the INSR is located within a cystein-rich region of the a-subunits. Alternative splicing of exon 11 generates two isoforms of the a-subunit which differ in their C-terminus and in their tissue distribution (type A leukocytes type B liver type A and B skeletal muscle and fat). The isoforms differ in their affinity to insulin (A > B), but then-relevance for normal and impaired insulin action is not entirely clear [1,2]. 

FIGURE 49-1. Normal glucose metabolism. Once insulin binds with receptors on the cell membrane, glucose can move into the cell, promoting cellular metabolism and energy production. 

Petruzzelli L, Herrera R, Arenas-Garcia R, Fernandez R, Bimbaum MJ, Rosen OM 1986 Isolation of a Drosophila genomic sequence homologous to the kinase domain of the human insulin receptor and detection of the phosphorylated Drosophila receptor with an anti-peptide antibody. Proc Natl Acad Sci USA 83 4710-4714 Podskalny J, McElduff A, Gorden P 1984 Insulin receptors on Chinese hamster ovary (CHO) cells altered insulin binding to glycosylation mutants. Biochem Biophys Res Commun 125 70-75... 

Podskalny J, McElduff A, Gorden P 1984 Insulin receptors on Chinese hamster ovary (CHO) cells altered insulin binding to glycosylation mutants. Biochem Biophys Res Commun 125 70-75... 

Rouiller DG, Sharon N, McElduff A, Podskalny JM, Gorden P 1986 Lectins as probes of insulin receptor carbohydrate composition studies in glycosylation mutants of Chinese hamster ovarian cells with altered insulin binding. Endocrinology 118 1159-1165... 

Insulin binding to the extracellular side of cell membranes initiates the insulin cascade , a series of phosphorylation/dephosphorylation steps. A postulated mechanism for vanadium is substitution of vanadate for phosphate in the transition state structure of protein tyrosine phosphatases (PTP).267,268 In normal physiological conditions, the attainable oxidation states of vanadium are V111, Viv and Vv. Relevant species in solution are vanadate, (a mixture of HV042-/ H2VOO and vanadyl V02+. Vanadyl is not a strong inhibitor of PTPs, suggesting other potential mechanisms for insulin mimesis for this cation. 

Store it while it s here. Insulin binds to a specific receptor on the cell surface and exerts its metabolic effect by a signaling pathway that involves a receptor tyrosine kinase phosphorylation cascade. Note that insulin stimulates storage processes and at the same time inhibits degradative pathways. 

The insulin receptor is a tetrameric integral membrane glycoprotein consisting of two 735 amino acid a-chains and two 620 amino acid P-chains. These are held together by disulfide linkages (Figure 11.2). The a-chain resides entirely on the extracellular side of the plasma membrane and contains the cysteine-rich insulin-binding domain. 

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

An important question arises about the effects of phospholipid composition and the function of membrane-bound enzymes. The phospholipid composition and cholesterol content in cell membranes of cultured cells can be modified, either by supplementing the medium with specific lipids or by incubation with different types of liposomes. Direct effects of phospholipid structure have been observed on the activity of the Ca2+-ATPase (due to changes in the phosphorylation and nucleotide binding domains) [37]. Evidence of a relationship between lipid structure and membrane functions also comes from studies with the insulin receptor [38]. Lipid alteration had no influence on insulin binding, but modified the kinetics of receptor autophosphorylation. 

Decreased insulin binding to the receptor Decreased numbers of receptors... 

Production of insulin is triggered when there is a rise in blood sugar, for example, after a meal. Most of our body cells have insulin receptors, which bind to the insulin secreted. When the insulin binds to the receptor, other receptors on the cell are activated to absorb sugar (glucose) from the bloodstream into the cell. 

Insulin binding activates the tyrosine kinase activity associated with the cytoplasmic domain of its receptor as shown in F jure 1-9-4. There is no trimeric G protein, enzyme, or second messenger required to activate this protein tyrosine kinase activity ... 

T --"v Insulin Binding I C I Activates Tyrosine Ls. i Kiease Activity... 

The insulin receptor protein represents a ligand-operated enzyme (C), a catalytic receptor. When insulin binds to the extracellular attachment site, a tyrosine kinase activity is "switched on at the intracellular portion. Protein phosphorylation leads to altered cell function via the assembly of other signal proteins. Receptors for growth hormones also belong to the catalytic receptor class. 

CN104 Pan, J. S., and C. D. Berdanier. Dietary fat saturation affects hepatocyte insulin binding and glucose metabolism in BHE rats. J Nutr 1991 121(11) 1820-1826. 

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. 

ST 13 fibroblasts maintained in a medium containing insulin differentiate into adipose-like cells. This conversion is characterized by the appearance of lipid droplets in the cytoplasm and by an increase in synthesis and accumulation of cellular triglyceride. The insulin binding increases about 10-fold during differentiation. Tunicamycin inhibits the differentiation and suppresses insulin-binding activity.551... 

Ottensmeyer FP et al Mechanism of transmembrane signalling Insulin binding and the insulin receptor. Biochemistry 2000 39 12103. [PMID ... 

Glnsenoslde Rg1 Increases the insulin binding In liver and brain mice membranes... 

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... 

The insulin receptor is the prototype for a number of receptor enzymes with a similar structure and receptor Tyr kinase activity. The receptors for epidermal growth factor and platelet-derived growth factor, for example, have structural and sequence similarities to the insulin receptor, and both have a protein Tyr kinase activity that phosphorylates IRS-1. Many of these receptors dimerize after binding ligand the insulin receptor is already a dimer before insulin binds. The binding of adaptor proteins such as Grb2 to (P) Tyr residues is a common mechanism for promoting protein-protein interactions, a subject to which we return in Section 12.5. 

When insulin binds to its receptor, each a/3 monomer of the receptor phosphorylates the /3 chain of its partner, activating the receptor s Tyr kinase activity. The kinase catalyzes the phosphorylation of T)yr residues on other proteins such as IRS-1. 

FIGURE 15-29 The path from insulin to GSK3 and glycogen synthase. Insulin binding to its receptor activates a tyrosine protein kinase in the receptor, which phosphorylates insulin receptor substrate-1 (IRS-1). The phosphotyrosine in this protein is then bound by phos-phatidylinositol 3-kinase (PI-3K), which converts phosphatidylinositol... 

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

Insulin binds to specific, high-affinity receptors in the cell membrane of most tissues, including liver, muscle, and adipose. This is the first step in a cascade of reactions ultimately leading to a diverse array of biologic actions. 

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