![Chemrec white](https://upload.wikimedia.org/wikipedia/commons/2/24/Chemrec_white.jpg)
Chemokine receptors are
cytokine receptor
Cytokine receptors are receptors that bind to cytokines.
In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly be ...
s found on the surface of certain cells that interact with a type of
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
called a
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 ...
.
There have been 20 distinct chemokine receptors discovered in humans.
Each has a
rhodopsin-like 7-
transmembrane
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
(7TM) structure and couples to
G-protein
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 ...
for
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
within a cell, making them members of a large protein family of
G protein-coupled receptor
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 ...
s. Following interaction with their specific chemokine
ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
s, chemokine receptors trigger a
flux
Flux describes any effect that appears to pass or travel (whether it actually moves or not) through a surface or substance. Flux is a concept in applied mathematics and vector calculus which has many applications to physics. For transport ph ...
in
intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
calcium (Ca
2+) ions (
calcium signaling
Calcium signaling is the use of calcium ions (Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Ca2+ is important for cellular signalling, for once it enters the cytosol of the cytoplasm it exerts allos ...
). This causes cell responses, including the onset of a process known as
chemotaxis
Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...
that traffics the cell to a desired location within the organism. Chemokine receptors are divided into different families,
CXC chemokine receptors
CXC chemokine receptors are integral membrane proteins that specifically bind and respond to cytokines of the CXC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are ...
,
CC chemokine receptors
CC chemokine receptors (or beta chemokine receptors) are integral membrane proteins that specifically bind and respond to cytokines of the CC chemokine family. They represent one subfamily of chemokine receptors, a large family ...
,
CX3C chemokine receptors and
XC chemokine receptors that correspond to the 4 distinct subfamilies of chemokines they bind. Four families of chemokine receptors differ in spacing of cysteine residues near N-terminal of the receptor.
Structural characteristics
Chemokine receptors are
G protein-coupled receptor
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 ...
s containing 7
transmembrane
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
domains
that are found predominantly on the surface of
leukocyte
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
s, making it one of the
rhodopsin-like receptors
Rhodopsin-like receptors are a family of proteins that comprise the largest group of G protein-coupled receptors.
Scope
G-protein-coupled receptors, GPCRs, constitute a vast protein family that encompasses a wide range of functions (including ...
. Approximately 19 different chemokine receptors have been characterized to date, which share many common structural features; they are composed of about 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 that are divided into a short and acidic N-terminal end, seven helical transmembrane domains with three
intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
and three
extracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
hydrophilic
A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press.
In contrast, hydrophobes are no ...
loops, and an intracellular C-terminus containing
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 −COOâ ...
residues that act as
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 ...
sites during receptor regulation. The first two extracellular loops of chemokine receptors are linked together by
disulfide bond
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 ...
ing between two conserved
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
residues. The
N-terminal
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 ami ...
end of a chemokine receptor binds to chemokines and is important for ligand specificity.
G-protein
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 ...
s couple to the C-terminal end, which is important for receptor signaling following ligand binding. Although chemokine receptors share high amino acid identity in their primary sequences, they typically bind a limited number of ligands.
Chemokine receptors are redundant in their function as more than one chemokine is able to bind to a single receptor.
Signal transduction
Intracellular signaling
In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
by chemokine receptors is dependent on neighbouring G-proteins. G-proteins exist as a heterotrimer; they are composed of three distinct subunits. When the molecule
GDP
Gross domestic product (GDP) is a monetary measure of the market value of all the final goods and services produced and sold (not resold) in a specific time period by countries. Due to its complex and subjective nature this measure is ofte ...
is bound to the G-protein subunit, the G-protein is in an inactive state. Following binding of the chemokine ligand, chemokine receptors associate with G-proteins, allowing the exchange of GDP for another molecule called
GTP, and the dissociation of the different G protein subunits. The subunit called Gα activates an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
known as
Phospholipase C
Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...
(PLC) that is associated with the
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
. PLC cleaves
Phosphatidylinositol (4,5)-bisphosphate
Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...
(PIP2) to form two
second messenger
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
molecules called
inositol triphosphate
Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the p ...
(IP3) and
diacylglycerol
A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as s ...
(DAG); DAG activates another enzyme called
protein kinase C
In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...
(PKC), and IP3 triggers the release of
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
from intracellular stores. These events promote many signaling cascades, effecting a cellular response.
For example, when CXCL8 (IL-8) binds to its specific receptors,
CXCR1
Interleukin 8 receptor, alpha is a chemokine receptor. This name and the corresponding gene symbol IL8RA have been replaced by the HGNC approved name C-X-C motif chemokine receptor 1 and the approved symbol CXCR1. It has also been designated as CD ...
or
CXCR2
Interleukin 8 receptor, beta is a chemokine receptor. ''IL8RB'' is also known as ''CXCR2'', and CXCR2 is now the IUPHAR Committee on Receptor Nomenclature and Drug classification-recommended name.
Function
The protein encoded by this gene is ...
, a rise in intracellular calcium activates the enzyme
phospholipase D (PLD) that goes on to initiate an intracellular signaling cascade called the
MAP kinase pathway. At the same time, the G-protein subunit Gα directly activates an enzyme called
protein tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
Tyrosine kinases belong to a larger cla ...
(PTK), which phosphorylates
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 −COOâ ...
residues in the tail of the chemokine receptor, causing its desensitisation or inactivation.
The initiated
MAP kinase
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses ...
pathway activates specific cellular mechanisms involved in
chemotaxis
Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...
,
degranulation, release of
superoxide
In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of the ...
anions, and changes in the avidity of
cell adhesion molecule
Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...
s called
integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
s.
[ Chemokines and their receptors play a crucial role in cancer metastasis as they are involved in extravasation, migration, micrometastasis, and angiogenesis.] This role of chemokine is strikingly similar to their normal function of localizing leukocytes to an inflammatory site.
Selective pressures on Chemokine receptor 5 (CCR5)
Human Immunodeficiency virus
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause AIDS, acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the ...
uses CCR5 receptor to target and infect host T-cells
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 ...
in humans. It weakens the immune system by destroying the CD4+ T-helper cells, making the body more susceptible to other infections. CCR5-Δ32 is an allelic variant of CCR5 gene with a 32 base pair deletion that results in a truncated receptor. People with this allele are resistant to AIDS as HIV cannot bind to the non-functional CCR5 receptor. An unusually high frequency of this allele is found in European Caucasian
Caucasian may refer to:
Anthropology
*Anything from the Caucasus region
**
**
** ''Caucasian Exarchate'' (1917–1920), an ecclesiastical exarchate of the Russian Orthodox Church in the Caucasus region
*
*
*
Languages
* Northwest Caucasian l ...
population, with an observed cline towards the north. Most researchers have attributed the current frequency of this allele to two major epidemics of human history: plague
Plague or The Plague may refer to:
Agriculture, fauna, and medicine
*Plague (disease), a disease caused by ''Yersinia pestis''
* An epidemic of infectious disease (medical or agricultural)
* A pandemic caused by such a disease
* A swarm of pes ...
and smallpox
Smallpox was an infectious disease caused by variola virus (often called smallpox virus) which belongs to the genus Orthopoxvirus. The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (WHO) c ...
. Although this allele originated much earlier, its frequency rose dramatically about 700 years ago. This led scientists to believe that bubonic plague acted as a selective pressure that drove CCR5-Δ32 to high frequency. It was speculated that allele may have provided protection against the ''Yersinia pestis
''Yersinia pestis'' (''Y. pestis''; formerly '' Pasteurella pestis'') is a gram-negative, non-motile, coccobacillus bacterium without spores that is related to both ''Yersinia pseudotuberculosis'' and ''Yersinia enterocolitica''. It is a facult ...
'', which is the causative agent for plague. Many in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
mouse studies have refuted this claim by showing no protective effects of CCR5-Δ32 allele in mice infected with ''Y. pestis''. Another theory that has gained more scientific support links the current frequency of the allele to smallpox epidemic. Although plague has killed a greater number people in a given time period, smallpox has collectively taken more lives. As smallpox
Smallpox was an infectious disease caused by variola virus (often called smallpox virus) which belongs to the genus Orthopoxvirus. The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (WHO) c ...
has been dated back to 2000 years, a longer time period would have given smallpox enough time to exert selective pressure given an earlier origin of CCR5-Δ32. Population genetic models that analyzed geographic and temporal distribution of both plague and smallpox provide a much stronger evidence for smallpox as the driving factor of CCR5-Δ32. Smallpox has a higher mortality rate than plague, and it mostly affects children under the age of ten. From an evolutionary viewpoint, this results in greater loss of reproductive potential from a population which may explain increased selective pressure by smallpox. Smallpox was more prevalent in regions where higher CCR5-Δ32 frequencies are seen. Myxoma
A myxoma (New Latin from Greek 'muxa' for mucus) is a myxoid tumor of primitive connective tissue. It is most commonly found in the heart (and is the most common primary tumor of the heart in adults) but can also occur in other locations.
Ty ...
and variola major
Smallpox was an infectious disease caused by variola virus (often called smallpox virus) which belongs to the genus Orthopoxvirus. The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (WHO) cer ...
belong to the same family of viruses and myxoma has been shown to use CCR5
C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines.
In humans, the ''CCR5'' gene that encodes the CCR5 p ...
receptor to enter its host. Moreover, ''Yersinia'' is a bacterium which is biologically distinct from viruses and is unlikely to have similar mechanism of transmission. Recent evidence provides a strong support for smallpox as the selective agent for CCR5-Δ32.
Families
* CXC chemokine receptors
CXC chemokine receptors are integral membrane proteins that specifically bind and respond to cytokines of the CXC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are ...
(six members)
* CC chemokine receptors
CC chemokine receptors (or beta chemokine receptors) are integral membrane proteins that specifically bind and respond to cytokines of the CC chemokine family. They represent one subfamily of chemokine receptors, a large family ...
(ten/eleven members)
* C chemokine receptors (one member, XCR1
The "C" sub-family of chemokine receptors contains only one member: XCR1, the receptor for XCL1 and XCL2
Chemokine (C motif) ligand 2 (XCL2) is a small cytokine belonging to the XC chemokine family that is highly related to another chemokine c ...
)
* CX3C chemokine receptors (one member, CX3CR1
CX3C motif chemokine receptor 1 (CX3CR1), also known as the fractalkine receptor or G-protein coupled receptor 13 (GPR13), is a transmembrane protein of the G protein-coupled receptor 1 (GPCR1) family and the only known member of the CX3C chemokin ...
)
Fifty chemokines have been discovered so far, and most bind onto CXC and CC families. Two types of chemokines that bind to these receptors are inflammatory chemokines and homeostatic chemokines. Inflammatory chemokines are expressed upon leukocyte activation, whereas homeostatic chemokines show continual expression.
References
External links
*
The Cytokine Receptor Database
{{Chemokine receptor modulators
Cell biology
Integral membrane proteins