Overview

The interleukin-8 receptors (IL-8R) are two

7-transmembrane G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

proteins in the G-protein coupled-receptor family: interleukin-8 receptor A (IL-8RA) and interleukin-8 receptor B (IL-8RB). These receptors are generally found on human

neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...

s, a type of white blood cell of the myeloid lineage, with approximately 65,000 receptors per neutrophil. Both receptors have a size of 60kDa, are

glycosylated Glycosylation is the reaction in which a carbohydrate (or 'glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not alw ...

(contains covalent attachments and modifications) and G-protein linked, and can cause an increase in intracellular Ca²⁺ levels. Binding of

Interleukin 8 Interleukin 8 (IL-8 or chemokine (C-X-C motif) ligand 8, CXCL8) is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage ...

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

Structure

IL-8 receptors are 7-transmembrane proteins; they contain 7

alpha helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...

that each span the thickness of the

phospholipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...

of a cell membrane. IL-8RA is a

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

of 350

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

s, and IL-8RB is composed of 355 amino acids. Receptors A and B share 78% of their sequence identity, and are considered to be the only two biologically significant receptors of IL-8. The genes for both receptors are located on chromosome 2q35 and are each encoded by a single

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

, 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. The reported size of the translated protein is approximately 40kD, 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.

N-terminus activity

The

amino terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

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 acidic residues, which correlate to their high binding affinities for IL-8, which is rich in basic residues. Asp11 on the N-terminus, Glu275 and Arg280 (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. These three residues are brought close together via a

disulfide bridge In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

C-terminus activity

The

carboxyl terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

of the receptors is located on the intracellular side of the protein, and is rich in

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...

and

threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO� ...

residues (a characteristic of many proteins of the 7-transmembrane G-protein coupled receptor family). The C-terminus is a target for

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

and exhibits

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

activity. This is the beginning of signaling pathways and phosphorylation cascades to recruit neutrophils and

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...

, the development and growth of new blood vessels.

Expression and function

Both IL-8RA and IL-8RB are expressed in

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also inf ...

macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...

basophil Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammator ...

T-lymphocytes A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...

, and

endothelial cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

. IL-8RB is expressed additionally in neurons of the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

. 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 CXC

chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...

family with lower affinity than IL-8 binding, exhibiting a "shared" binding behavior.

Chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...

s 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. 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 heterotrimeric

G-proteins G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...

(a typical effect of ligands binding to 7TM G-protein coupled receptors), thereby activating them. 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.

References

External links

* {{Interleukin receptor modulators Chemokine receptors