Insulin receptor (IR) is a transmembrane receptor that is activated insulin, IGF-I, the IGF-II, belong to a large group of tyrosine kinase receptors. Conditions, metabolism, insulin receptor, plays an important role in the deallocation process can lead to a number of clinical conditions, including cancer and diabetes in the regulation of glucose homeostasis. Biochemically, the insulin receptor, results using the IR-B isoforms or IR splicing during transcription of another, which are encoded by genes INSR single. Homo-or hetero-generate after isoforms result formation down of proteolytic cleavage, the β subunit of post-translational events and α, the 320 kDa of ≈ of transmembrane receptor insulin May combination, disulfide-linked eventually dimerization.
First, the transfer of the splice variant of alternative gene INSR derived, it is translated to form one of the monomers 2 and IR, wherein exon 11 is turned off, exon 11 is included IR-B. I include the exon 11 that results in the addition of 12 amino acids upstream of the inheritance Flynn protyolytic the cleavage site. It is the 12 additional amino acids still present in the C-terminus of the assumed interfering with ligand interactions of α – chain in receptor dimerization, and protyolyticα-cutting after β-strand, these receptors . Made (310 CR, from the remaining 158), extra leucine-rich repeat domain, from three fibronectin type III domain region leucine-rich repeat domain, rich cyctine is divided into eight areas of the structure, each isometric monomer, FNIII-1, and 3 FNIII-FNIII-2. Also includes bringing the proteolysis of both the domain and IDβ resident FNIII-2α/IDα the input domain is a β Flynn cleavage site. In the β chain, downstream FNIII-3 domain, area intracellular membrane vicinity of (JM) (TH) and responsibility intracellular tyrosine kinase intracellular signaling pathways upstream then transmembrane helices (TK) catalytic domain immediately is.
Covalent bond chain two disulfide bonds after the cleaved β chain, the monomer to dimer or hetero-receptor homo and the corresponding α-, of one disulfide bond between the monomer of each dimer extends from the α chain It is maintained between. Three-dimensional structure ectodomain general having 4 ligand binding site, such as a reverse “V” was each monomer, and FNIII-1 domain of each monomer constituting the inverted “V and L2 inverse” V ” The endogenous ligand of the insulin receptor, which contains the IGF-II Insulin and IGF-I. top rotates about the about twice an axis parallel to, ligand binding IR ectodomain of the α-chain As a result of the autophosphorylation of tyrosine residues in a variety of intracellular domain of the βTK, for example, changing chains thereof to induce a conformational change of the receptor, specific insulin receptor substrate proteins, such as (IRS) In addition to promote the recruitment of adapter proteins, of Src, the Src homology 2, – including protein phosphatase PTP1B B (SH2-B), and APS, downstream of the process of publicity glucose homeostasis them eventually.
More precisely, the relationship between a ligand and IR indicate a complex allosteric properties. This measurement of the ratio of bound ligand IR free ligand Scatchard plots that do not follow a linear relationship with respect to a change in the concentration of bound ligand IR by means corresponding to the IR has been found It is shown using the dissociation rate of the IR-ligand, initially differently above, and suggests that the nature of this cooperation is negative, binding of a ligand, by addition of free ligand further title ligand binding relationship Cooperative inhibits binding further active site of her second observation that IR is promoted, -. Allosteric inhibition Exhibition. Is a structure that has not been elucidated yet the exact mechanism of ligand binding and IR, but is determined by the (insulin / IGF-I) prediction related systems biology approach biological dynamics of IR-ligand, etc. But, the available IR ectodomain structure that are currently been identified in context.
These models may have a portion 1, a 2 IR insulin binding sites each monomer binds to the surface of insulin binding “classic” was shown. FNIII -2 and FNIII-1 consisting of the site and 2 L1 plus αCT domain consists of a junction of the line, expected to binding of insulin to the ‘new’ six-sided binding site. Each monomer, so contributes to the addition of the exhibit “mirror” of the IR ectodomain, when applied to any monomer, the N-terminal portion 1 of the monomers 3D, one which C a second monomer finally (opposite side of the ectodomain structure that reflects inner) addition that faces the terminal portion 2. In the current literature, by determining the position of the second monomer, unlike the complement binding site, is the site 1 “2 Site” and each location the four sites and three named or site one or two.
Thus, the IR, e.g., 1, 2, instead of (4/2 “) or (3/1), these references (having a bond two surfaces) through four sites We show that it is possible to associate the insulin molecule. 1 Site 2 each site, so that faces proximally of the binding of insulin to the specific site, the ligand monomer over between “crosslinking” is generated and the expected of IR-insulin kinetics of the monomer, and its ligand IR have a post-crosslinking important insulin, one. intracellular tyrosine phosphorylation events physical effects. crosslinking that smaller 2 after binding of the ligand to the IR should follow (ie, these events of receptor observation of the above cooperation of negative between The making ectodomain structure that is required to act as a requirement for the maintenance of homeostasis of blood glucose and possibly activation) in order.
The main activities of the activation of the insulin receptor is the induction of glucose. Thus, leading to the insulin receptor and type 2 diabetes “insulin insensitivity” Signaling Reduction – No cells are able to take the (increase in circulating glucose) results in hyperglycemia and glucose, so that all results from diabetes. You may acanthosis nigricans of black skin is displayed patients with insulin resistance.
Some patients with homozygous mutation in the gene are described in INSR cause leprechaunism or Donohue syndrome. Dysfunction completely, this autosomal recessive genetic disease resulting in insulin receptor. Low setting, these patients have a severe growth retardation bulging, ears, nostrils dilated cardiomyopathy, a thickening lips often. In most cases, death occurs within a year of the first life, the prognosis of these patients is very poor. Other mutations, causing the expansion of the pineal gland serious Rabson-Mendenhall syndrome, hypertrophy and gums (gingiva) about patient has a tooth unusual feature in the same gene. Exhibit a variation in the level of glucose both diseases is: after eating glucose, first is very high, dropped to an abnormally low level then rapidly.
It functions as an intracellular second messenger to promote transcription of IRS-1 insulin regulatory gene is activated. First, SH2 of Grb2 protein binds to P-tyrosine residue of IRS-1 to consumers. Then, entering the nucleus, SOS which catalyzes the exchange of bound GDP by GTP on Ras in turn, the protein capable of binding to Protein G, the phosphorylation of mitogen-activated protein kinase nuclear various transcription factors then Grb2 I start the phosphorylation cascade that ends with activation.
Glycogen synthesis is stimulated by insulin receptor via IRS-1. In this case, this is the SH2 domain of PI-3 kinase that binds to P-Tyr of the IRS-1. Now, phosphatidylinositol 3,4,5 – 4,5 membrane lipid phosphatidylinositol triphosphate to – in order to be converted to bis-phosphate is activated, and PI-3K. This activates the (act) protein kinase, PKB through phosphorylation indirectly. PKB then, I to phosphorylate glycogen synthase including kinase-3, the number of the target protein. I am responsible for glycogen synthase (inactivated by it) and phosphorus to GSK-3. If the GSK-3 is phosphorylated, it is deactivated, it is possible to prevent the deactivation of glycogen synthase. In this roundabout, insulin, increased synthesis of glycogen.
Is fixed to the receptor on the insulin molecule, is performing the operation, there may be exacerbated by the cell, or may be released into the extracellular environment. Typically, degradation, including endocytosis of the insulin receptor complex following the action of the insulin-degrading enzyme. Insulin most molecules are degraded by hepatocytes. It is estimated that 71 minutes after the release of the first into the circulation of the insulin molecule typical, this is, and has deteriorated in the end.