Инсулин рецепторы: құрылымы мен функциясы

Mammalian protein found in Homo sapiens

The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF I, IGF II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeostasis; a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer. Insulin signalling controls access to blood glucose in body cells. When insulin falls, especially in those with high insulin sensitivity, body cells begin only to have access to lipids that do not require transport across the membrane. So, in this way, insulin is the key regulator of fat metabolism as well. Biochemically, the insulin receptor is encoded by a single gene , from which alternate splicing during transcription results in either IR A or IR B isoforms. Downstream post translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero dimerisation to produce the ≈320 kDa disulfide linked transmembrane insulin receptor. Each isometric monomer is structurally organized into 8 distinct domains consists of; a leucine rich repeat domain (L1, residues 1–157), a cysteine rich region (CR, residues 158–310), an additional leucine rich repeat domain (L2, residues 311–470), three fibronectin type III domains; FnIII 1 (residues 471–595), FnIII 2 (residues 596–808) and FnIII 3 (residues 809–906). Additionally, an insert domain (ID, residues 638–756) resides within FnIII 2, containing the α/β furin cleavage site, from which proteolysis results in both IDα and IDβ domains. Within the β chain, downstream of the FnIII 3 domain lies a transmembrane helix (TH) and intracellular juxtamembrane (JM) region, just upstream of the intracellular tyrosine kinase (TK) catalytic domain, responsible for subsequent intracellular signaling pathways. Upon cleavage of the monomer to its respective α and β chains, receptor hetero or homo dimerisation is maintained covalently between chains by a single disulphide link and between monomers in the dimer by two disulphide links extending from each α chain. The overall 3D ectodomain structure, possessing four ligand binding sites, resembles an inverted 'V', with the each monomer rotated approximately 2 fold about an axis running parallel to the inverted 'V' and L2 and FnIII 1 domains from each monomer forming the inverted 'V's apex.

The insulin receptor's endogenous ligands include insulin, IGF I and IGF II. Using a cryo EM, structural insight into conformational changes upon insulin binding was provided. Binding of ligand to the α chains of the IR dimeric ectodomain shifts it from an inverted V shape to a T shaped conformation, and this change is propagated structurally to the transmembrane domains, which get closer, eventually leading to autophosphorylation of various tyrosine residues within the intracellular TK domain of the β chain. Strictly speaking the relationship between IR and ligand shows complex allosteric properties. This was indicated with the use of a Scatchard plots which identified that the measurement of the ratio of IR bound ligand to unbound ligand does not follow a linear relationship with respect to changes in the concentration of IR bound ligand, suggesting that the IR and its respective ligand share a relationship of cooperative binding. Furthermore, the observation that the rate of IR ligand dissociation is accelerated upon addition of unbound ligand implies that the nature of this cooperation is negative; said differently, that the initial binding of ligand to the IR inhibits further binding to its second active site exhibition of allosteric inhibition.

The insulin receptor is a type of tyrosine kinase receptor, in which the binding of an agonistic ligand triggers autophosphorylation of the tyrosine residues, with each subunit phosphorylating its partner. The addition of the phosphate groups generates a binding site for the insulin receptor substrate (IRS 1), which is subsequently activated via phosphorylation. The activated IRS 1 initiates the signal transduction pathway and binds to phosphoinositide 3 kinase (PI3K), in turn causing its activation. This then catalyses the conversion of Phosphatidylinositol 4,5 bisphosphate into Phosphatidylinositol 3,4,5 trisphosphate (PIP3). PIP3 acts as a secondary messenger and induces the activation of phosphatidylinositol dependent protein kinase, which then activates several other kinases – most notably protein kinase B, (PKB, also known as Akt). PKB triggers the translocation of glucose transporter (GLUT4) containing vesicles to the cell membrane, via the activation of SNARE proteins, to facilitate the diffusion of glucose into the cell. PKB also phosphorylates and inhibits glycogen synthase kinase, which is an enzyme that inhibits glycogen synthase. Therefore, PKB acts to start the process of glycogenesis, which ultimately reduces blood glucose concentration.

The activated IRS 1 acts as a secondary messenger within the cell to stimulate the transcription of insulin regulated genes. First, the protein Grb2 binds the P Tyr residue of IRS 1 in its SH2 domain. Grb2 is then able to bind SOS, which in turn catalyzes the replacement of bound GDP with GTP on Ras, a G protein. This protein then begins a phosphorylation cascade, culminating in the activation of mitogen activated protein kinase (MAPK), which enters the nucleus and phosphorylates various nuclear transcription factors (such as Elk1).

Glycogen synthesis is also stimulated by the insulin receptor via IRS 1. In this case, it is the SH2 domain of PI 3 kinase (PI 3K) that binds the P Tyr of IRS 1. Now activated, PI 3K can convert the membrane lipid phosphatidylinositol 4,5 bisphosphate (PIP2) to phosphatidylinositol 3,4,5 triphosphate (PIP3). This indirectly activates a protein kinase, PKB (Akt), via phosphorylation. PKB then phosphorylates several target proteins, including glycogen synthase kinase 3 (GSK 3). GSK 3 is responsible for phosphorylating (and thus deactivating) glycogen synthase. When GSK 3 is phosphorylated, it is deactivated, and prevented from deactivating glycogen synthase. In this roundabout manner, insulin increases glycogen synthesis.

Once an insulin molecule has docked onto the receptor and effected its action, it may be released back into the extracellular environment or it may be degraded by the cell. Degradation normally involves endocytosis of the insulin receptor complex followed by the action of insulin degrading enzyme. Most insulin molecules are degraded by liver cells. It has been estimated that a typical insulin molecule is finally degraded about 71 minutes after its initial release into circulation.

Besides the metabolic function, insulin receptors are also expressed on immune cells, such as macrophages, B cells, and T cells. On T cells, the expression of insulin receptors is undetectable during the resting state but up regulated upon T cell receptor (TCR) activation. Indeed, insulin has been shown when supplied exogenously to promote in vitro T cell proliferation in animal models. Insulin receptor signalling is important for maximizing the potential effect of T cells during acute infection and inflammation.

The main activity of activation of the insulin receptor is inducing glucose uptake. For this reason "insulin insensitivity", or a decrease in insulin receptor signaling, leads to diabetes mellitus type 2 – the cells are unable to take up glucose, and the result is hyperglycemia (an increase in circulating glucose), and all the sequelae that result from diabetes. Patients with insulin resistance may display acanthosis nigricans. A few patients with homozygous mutations in the INSR gene have been described, which causes Donohue syndrome or Leprechaunism. This autosomal recessive disorder results in a totally non functional insulin receptor. These patients have low set, often protuberant, ears, flared nostrils, thickened lips, and severe growth retardation. In most cases, the outlook for these patients is extremely poor, with death occurring within the first year of life. Other mutations of the same gene cause the less severe Rabson Mendenhall syndrome, in which patients have characteristically abnormal teeth, hypertrophic gingiva (gums), and enlargement of the pineal gland. Both diseases present with fluctuations of the glucose level: After a meal the glucose is initially very high, and then falls rapidly to abnormally low levels. Other genetic mutations to the insulin receptor gene can cause Severe Insulin Resistance.