Insulin receptor
| Insulin receptor | ||
|---|---|---|
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Existing structural data: s. UniProt |
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| Properties of human protein | ||
| Mass / length primary structure | 2702 = 2 * 731 + 2 * 620 amino acids | |
| Secondary to quaternary structure | 2α + 2β single pass receptor | |
| Precursor | α + β | |
| Isoforms | Long, short | |
| Identifier | ||
| Gene names | INSR ; CD220 | |
| External IDs | ||
| Enzyme classification | ||
| EC, category | 2.7.10.1 , tyrosine kinase | |
| Response type | Phosphorylation | |
| Substrate | ATP + protein L-Tyr | |
| Products | ADP + Protein-L-Tyr-Phosphate | |
| Occurrence | ||
| Homology family | Insulin receptor | |
| Parent taxon | Chordates | |
| Orthologue | ||
| human | House mouse | |
| Entrez | 3643 | 16337 |
| Ensemble | ENSG00000171105 | ENSMUSG00000005534 |
| UniProt | P06213 | P15208 |
| Refseq (mRNA) | NM_000208 | NM_010568 |
| Refseq (protein) | NP_00019 | NP_034698 |
| Gene locus | Chr 19: 7.11 - 7.29 Mb | Chr 8: 3.15 - 3.28 Mb |
| PubMed search | 3643 |
16337
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The insulin receptor (IR) ( gene : INSR ) is the membrane protein to which released insulin binds and which makes it effective. The IR is produced in all chordates and expressed in different numbers by almost all cells. For example, the red blood cells express only a few hundred receptors, while liver cells and fat cells express several hundred thousand. Mutations in the INSR gene are responsible for hereditary insulin resistance , Rabson-Mendenhall syndrome , Donahue syndrome , insulin-independent diabetes mellitus , familial hypoglycemia and diabetes mellitus with acanthosis nigricans .
structure
The insulin receptors are located within the cell membrane and thus belong to the group of transmembrane receptors or integral membrane proteins .
It is a heterotetramer , which is composed of 2 α and 2 β subunits: an extracellular α subunit and a β subunit that spans the cell membrane, a large part of which is located inside the cell. The α and β subunits are each covalently linked to one another by disulfide bridges . The β subunits have a so-called tyrosine kinase activity. This means that they are able to phosphorylate tyrosine residues . The phosphate group comes from an ATP molecule.
Insulin Binding and Autophosphorylation
When an insulin molecule is bound by the two α subunits, a change in conformation occurs . The two β-subunits approach each other and phosphorylate each other. Therefore it is a trans-autophosphorylation. The kinase domains of the β subunits undergo a conformational change as a result of phosphorylation and are thereby activated.
If the tyrosine kinase of the insulin receptor has assumed its active state after insulin binding and activation, several receptor subunits near the kinase domain are phosphorylated and now represent binding sites for intracellular substrates (e.g. insulin receptor substrates , IRS). IRS are so-called adapter proteins between the insulin receptor and the protein that forwards the signaling cascade (e.g. phosphoinoside kinase-3).
Furthermore, endocytosis of the entire area takes place within a few minutes, as a result of which the kinase activity of the receptor is carried into the cytosol . After the effect is done, the receptor is recycled.
Ultimately, the binding of insulin to its receptor triggers several kinase cascades (cascade of phosphorylation reactions) that can be described by signaling pathways.
Activated signaling pathways
The insulin signal is coupled to various intracellular signal cascades through the formation of signal complexes . These signaling pathways trigger diverse processes in the cell, such as rapid glucose processing, lipid and protein metabolism, as well as the gene expression required for this .
MAP kinase cascade
This pathway activates protein synthesis via phosphorylation of the SHC-transforming protein , SOS-GRB2-modulated activation of Ras and subsequently Raf , and subsequent MAP kinase cascade.
Insulin receptor-substrate cascade
About above IRS adapter proteins is phosphoinositide 3-kinase is activated, which in turn for PI3-cascade with activation of protein kinase B leads (PKB), which phosphorylates several target proteins. Phosphorylation of the glycogen synthase kinase 3 deactivates them, whereby ongoing phosphorylation of the UDP glycogen synthase does not take place, whereby it is activated. Possible phosphorylation of the insulin-stimulated protein kinase (ISPK, RSK2) phosphorylates and activates the protein phosphatase PP1G . PP1G dephosphorylates glycogen phosphorylase, which in turn is deactivated. Through this process, glucose (with a high energy charge ) is added to the glycogen store.
PKB also causes vesicles with the glucose transporter 4 (GLUT4), which is otherwise not present on the cell surface, to fuse with the cell membrane in muscle and fat cells. This makes GLUT4 functional and more glucose can be used for energy production. This mechanism lowers the blood glucose level quickly and effectively. But GLUT4 is also activated in another way.
SH2 adapter protein cascade
The phosphorylation of SH2 adapter protein 2 (APS) and further activation of Cbl, GRF2, Tc10, CIP4 / 2 intensifies the mobilization of GLUT4 vesicles with the following massive import of glucose into the cell.
The routes outlined thus cause the blood glucose level to drop
- Promotion of glucose uptake (GLUT4 translocation to the cell surface)
- Promotes glucose storage ( glycogen synthesis ) in the liver and muscles
This signal is supported by switching on glucose-consuming pathways. Further supportive measures consist in switching off glucose-supplying routes, for example by breaking down the second messenger cAMP via a phosphodiesterase (PDE).
Recycling the internalized receptor
The phosphorylated receptor molecule bound to insulin is located in a vesicle floating in the cytosol, the endocytosis of which is complete after five minutes. In addition to proton pumps, the vesicle already contains insulin-degrading enzymes. The proton pumps lower the pH in the vesicle from 7.4 to 6.0, which causes the insulin to separate from the receptor and break down. When insulin is no longer able to maintain the signal, protein tyrosine phosphatases are able to dephosphorylate the receptor. An acidic environment finally causes the vesicle to reintegrate into the cell membrane with the recycled receptor.
Individual evidence
- ↑ UniProt P06213
- ↑ a b c d Stryer, Biochemie (6th edition), Spektrum-Verlag
- ↑ AP Bevan / reactome.org: Internalization of the insulin receptor
- ^ AP Bevan / reactome.org: Insulin receptor recycling
- ↑ Saltiel AR, Kahn CR: Insulin signaling and the regulation of glucose and lipid metabolism Nature. 2001 Dec 13; 414 (6865): 799-806. PMID 11742412
- ↑ AP Bevan / reactome.org: SHC-related events ( page no longer available , search in web archives ) Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice.
- ↑ Nasi / Annibali / reactome.org: ERK / MAPK targets
- ↑ a b c d KEGG: Insulin Signaling pathway
- ^ AP Bevan / reactome.org: IRS-related events
- ^ AP Bevan / reactome.org: Insulin receptor recycling
