| Interleukin-8 Receptor, alpha | |
|---|---|
| Identifiers | |
| Symbol | IL8RA |
| Alt. symbols | CMKAR1, CXCR1, CKR-1, CDw128a, CD181 |
| Other data | |
| Locus | Chr. 2q35 |
| Interleukin-8 Receptor, beta | |
|---|---|
| Identifiers | |
| Symbol | IL8RB |
| Alt. symbols | CXCR2, CKR-2, CDw128b |
| Other data | |
| Locus | Chr. 2q35 |
Theinterleukin-8 receptors (IL-8R) are two7-transmembrane proteins in theG-protein coupled-receptor family:[1] interleukin-8 receptor A (IL-8RA) and interleukin-8 receptor B (IL-8RB). These receptors are generally found on humanneutrophils, a type of white blood cell of themyeloid lineage, with approximately 65,000 receptors per neutrophil.[1] Both receptors have a size of 60kDa,[2] areglycosylated (contains covalent attachments and modifications) andG-protein linked, and can cause an increase in intracellular Ca2+ levels. Binding ofInterleukin 8 leads to activation of the cell (commonly a neutrophil), allowing it to recruit more white blood cells to the site of Interleukin 8 release and to produce enzymes that would assist in the destruction of foreign material at the site of infection[3][4]
IL-8 receptors are 7-transmembrane proteins; they contain 7alpha helices that each span the thickness of thephospholipid bilayer of a cell membrane. IL-8RA is apeptide of 350amino acids, and IL-8RB is composed of 355 amino acids.[2] Receptors A and B share 78% of their sequence identity, and are considered to be the only two biologically significant receptors of IL-8.[5] The genes for both receptors are located on chromosome 2q35[5] and are each encoded by a singleexon, and are 20 kb apart in distance. The close proximity and location of these two genes on the chromosome suggest that they are derived from the same ancestor sequence.[1] The reported size of the translated protein is approximately 40kD,[6] differing from the native purified receptors from the surface of neutrophils by 20kD. This difference could be due to the N-terminus glycosylations that occur post-translation and contribute to an increase in apparent size of the mature receptor.[6]
Theamino terminus of the receptors is located on the extracellular side of the protein, and function to determine the binding specificity of ligands to the receptor. The N-terminus of both receptors A and B are rich in acidicresidues, which correlate to their high binding affinities for IL-8, which is rich in basic residues.Asp11 on the N-terminus,Glu275 andArg280 (both on the loop between the 7th and 6th transmembrane domains) are the three main peptide residues that participate in ligand binding on IL-8A. IL-8B shows a similar binding structure.[2] These three residues are brought close together via adisulfide bridge.[1]
Thecarboxyl terminus of the receptors is located on the intracellular side of the protein, and is rich inserine andthreonine residues (a characteristic of many proteins of the 7-transmembrane G-protein coupled receptor family). The C-terminus is a target forphosphorylation and exhibitskinase activity. This is the beginning of signaling pathways and phosphorylation cascades to recruit neutrophils andangiogenesis, the development and growth of new blood vessels.[2]
Both IL-8RA and IL-8RB are expressed inneutrophils,monocytes,macrophages,basophils,T-lymphocytes, andendothelial cells. IL-8RB is expressed additionally in neurons of thecentral nervous system. IL-8RA is highly specific for interleukin-8 and only responds when this particular ligand is bound to its receptor site, exhibiting "specific" binding behavior. IL-8RB binds to IL-8 with the same affinity as IL-8RA, but also binds to neutrophil-activating protein 2 (NAP-2) and other small receptor molecules of the CXCchemokine family with lower affinity than IL-8 binding, exhibiting a "shared" binding behavior.[1]Chemokines are a class of small molecules that induce the recruitment of leukocytes and stimulate pro-inflammatory responses; the responsiveness of IL-8R to chemokines suggests that is heavily involved in recruitment of white blood cells for inflammatory and immunological response purposes.[4]
The binding of IL-8 to the receptor induces the following three main responses in neutrophils, all of which assist a neutrophil in developing molecular mechanisms to target and kill pathogens: shape and conformational change of the neutrophil (which allows for transendothelial migration of the cell), degranulation (causing the release of enzymes within the cell), and the dissociation of heterotrimericG-proteins (a typical effect of ligands binding to 7TM G-protein coupled receptors), thereby activating them.[4] The activation of G-proteins leads to signal transduction and phosphorylation cascades, with the ultimate effect of changing gene expression of the neutrophil to allow for recruitment of other white blood cells to the local area.[3]