Chemokine receptor

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Typical structure of a chemokine receptor, with seven transmembrane helices and a characteristic "DRY" motif in the second intracellular loop. Chemokine receptors are usually linked to a G-protein through which they signal. Chemrec white.jpg
Typical structure of a chemokine receptor, with seven transmembrane helices and a characteristic "DRY" motif in the second intracellular loop. Chemokine receptors are usually linked to a G-protein through which they signal.
Chemokine receptor family
Identifiers
SymbolChemokine_rcpt
InterPro IPR000355

Chemokine receptors are cytokine receptors found on the surface of certain cells that interact with a type of cytokine called a chemokine. [1] [2] There have been 20 distinct chemokine receptors discovered in humans. [3] Each has a rhodopsin-like 7-transmembrane (7TM) structure and couples to G-protein for signal transduction within a cell, making them members of a large protein family of G protein-coupled receptors. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium (Ca2+) ions (calcium signaling). This causes cell responses, including the onset of a process known as chemotaxis that traffics the cell to a desired location within the organism. Chemokine receptors are divided into different families, CXC chemokine receptors, CC chemokine receptors, CX3C chemokine receptors and XC chemokine receptors that correspond to the 4 distinct subfamilies of chemokines they bind. The four subfamilies of chemokines differ in the spacing of structurally important cysteine residues near the N-terminal of the chemokine. [4]

Contents

Structural characteristics

Chemokine receptors are G protein-coupled receptors containing 7 transmembrane helices [5] that are found predominantly on the surface of leukocytes. Approximately 19 different chemokine receptors have been characterized to date, which share many common structural features. They are composed of about 350 amino acids that are divided into a short and acidic N-terminal end, seven transmembrane helices with three intracellular and three extracellular hydrophilic loops, and an intracellular C-terminus containing serine and threonine residues that act as phosphorylation sites during receptor regulation. The first two extracellular loops of chemokine receptors are linked together by disulfide bonding between two conserved cysteine residues. The N-terminal end of a chemokine receptor binds to chemokines and is important for ligand specificity. G-proteins 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. [6] Chemokine receptors are redundant in their function as more than one chemokine is able to bind to a single receptor. [4]

Signal transduction

Intracellular signaling 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 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 known as Phospholipase C (PLC) that is associated with the cell membrane. PLC cleaves Phosphatidylinositol (4,5)-bisphosphate (PIP2) to form two second messenger molecules called inositol triphosphate (IP3) and diacylglycerol (DAG); DAG activates another enzyme called protein kinase C (PKC), and IP3 triggers the release of calcium from intracellular stores. These events promote many signaling cascades, effecting a cellular response. [7]

For example, when CXCL8 (IL-8) binds to its specific receptors, CXCR1 or CXCR2, 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 (PTK), which phosphorylates serine and threonine residues in the tail of the chemokine receptor, causing its desensitisation or inactivation. [7] The initiated MAP kinase pathway activates specific cellular mechanisms involved in chemotaxis, degranulation, release of superoxide anions, and changes in the avidity of cell adhesion molecules called integrins. [6] Chemokines and their receptors play a crucial role in cancer metastasis as they are involved in extravasation, migration, micrometastasis, and angiogenesis. [4] This role of chemokine is strikingly similar to their normal function of localizing leukocytes to an inflammatory site. [4]

Selective pressures on Chemokine receptor 5 (CCR5)

Human Immunodeficiency virus uses CCR5 receptor to target and infect host T-cells 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 population, with an observed cline towards the north. [8] Most researchers have attributed the current frequency of this allele to two major epidemics of human history: plague and smallpox. Although this allele originated much earlier, its frequency rose dramatically about 700 years ago. [8] 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 , which is the causative agent for plague. Many in vivo mouse studies have refuted this claim by showing no protective effects of CCR5-Δ32 allele in mice infected with Y. pestis. [9] [10] 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. [8] As smallpox 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. [8] 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. [8] Smallpox has a higher mortality rate than plague, and it mostly affects children under the age of ten. [8] 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 and variola major belong to the same family of viruses and myxoma has been shown to use CCR5 receptor to enter its host. [11] 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

Fifty chemokines have been discovered so far, and most bind onto CXC and CC families. [4] 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. [3]

Related Research Articles

<span class="mw-page-title-main">G protein-coupled receptor</span> Class of cell surface receptors coupled to G-protein-associated intracellular signaling

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 proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. They are coupled with G proteins. They pass through the cell membrane seven times in the form of six loops of amino acid residues, which is why they are sometimes referred to as seven-transmembrane receptors. Ligands can bind either to the extracellular N-terminus and loops or to the binding site within transmembrane helices. They are all activated by agonists, although a spontaneous auto-activation of an empty receptor has also been observed.

<span class="mw-page-title-main">Receptor (biochemistry)</span> Protein molecule receiving signals for a cell

In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a receptor and produce physiological responses such as change in the electrical activity of a cell. For example, GABA, an inhibitory neurotransmitter, inhibits electrical activity of neurons by binding to GABAA receptors. There are three main ways the action of the receptor can be classified: relay of signal, amplification, or integration. Relaying sends the signal onward, amplification increases the effect of a single ligand, and integration allows the signal to be incorporated into another biochemical pathway.

<span class="mw-page-title-main">Chemokine</span> Small cytokines or signaling proteins secreted by cells

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 addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers.

<span class="mw-page-title-main">CCR5</span> Immune system protein

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.

Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. Second messengers trigger physiological changes at cellular level such as proliferation, differentiation, migration, survival, apoptosis and depolarization.

<span class="mw-page-title-main">CXCR4</span> Protein

C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene. The protein is a CXC chemokine receptor.

<span class="mw-page-title-main">CCL5</span> Mammalian protein found in humans

Chemokine ligand 5 is a protein which in humans is encoded by the CCL5 gene. The gene has been discovered in 1990 by in situ hybridisation and it is localised on 17q11.2-q12 chromosome.

<span class="mw-page-title-main">Macrophage inflammatory protein</span> Protein family

Macrophage Inflammatory Proteins (MIP) belong to the family of chemotactic cytokines known as chemokines. In humans, there are two major forms, MIP-1α and MIP-1β, renamed CCL3 and CCL4 respectively, since 2000. However, other names are sometimes encountered in older literature, such as LD78α, AT 464.1 and GOS19-1 for human CCL3 and AT 744, Act-2, LAG-1, HC21 and G-26 for human CCL4. Other macrophage inflammatory proteins include MIP-2, MIP-3 and MIP-5.

<span class="mw-page-title-main">CCL7</span> Mammalian protein found in Homo sapiens

Chemokine ligand 7 (CCL7) is a small cytokine that was previously called monocyte-chemotactic protein 3 (MCP3). CCL7 is a small protein that belongs to the CC chemokine family and is most closely related to CCL2.

<span class="mw-page-title-main">CCL8</span> Mammalian protein found in Homo sapiens

Chemokine ligand 8 (CCL8), also known as monocyte chemoattractant protein 2 (MCP2), is a protein that in humans is encoded by the CCL8 gene.

<span class="mw-page-title-main">CXCL9</span> Mammalian protein found in Homo sapiens

Chemokine ligand 9 (CXCL9) is a small cytokine belonging to the CXC chemokine family that is also known as monokine induced by gamma interferon (MIG). The CXCL9 is one of the chemokine which plays role to induce chemotaxis, promote differentiation and multiplication of leukocytes, and cause tissue extravasation.

<span class="mw-page-title-main">CXCL11</span> Mammalian protein found in Homo sapiens

C-X-C motif chemokine 11 (CXCL11) is a protein that in humans is encoded by the CXCL11 gene.

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 known as seven transmembrane (7-TM) proteins, since they span the cell membrane seven times. There are currently six known CXC chemokine receptors in mammals, named CXCR1 through CXCR6.

CC 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 of G protein-linked receptors that are known as seven transmembrane (7-TM) proteins since they span the cell membrane seven times. To date, ten true members of the CC chemokine receptor subfamily have been described. These are named CCR1 to CCR10 according to the IUIS/WHO Subcommittee on Chemokine Nomenclature.

<span class="mw-page-title-main">CXCR3</span> Protein-coding gene in humans

Chemokine receptor CXCR3 is a Gαi protein-coupled receptor in the CXC chemokine receptor family. Other names for CXCR3 are G protein-coupled receptor 9 (GPR9) and CD183. There are three isoforms of CXCR3 in humans: CXCR3-A, CXCR3-B and chemokine receptor 3-alternative (CXCR3-alt). CXCR3-A binds to the CXC chemokines CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (I-TAC) whereas CXCR3-B can also bind to CXCL4 in addition to CXCL9, CXCL10, and CXCL11.

<span class="mw-page-title-main">Interleukin 8 receptor, beta</span> Mammalian protein found in Homo sapiens

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.

<span class="mw-page-title-main">CXCR6</span> Mammalian protein found in Homo sapiens

C-X-C chemokine receptor type 6 is a protein that in humans is encoded by the CXCR6 gene. CXCR6 has also recently been designated CD186.

<span class="mw-page-title-main">G protein-coupled receptor kinase 3</span> Protein-coding gene in the species Homo sapiens

G-protein-coupled receptor kinase 3 (GRK3) is an enzyme that in humans is encoded by the ADRBK2 gene. GRK3 was initially called Beta-adrenergic receptor kinase 2 (βARK-2), and is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases that is most highly similar to GRK2.

Immunology is the study of the immune system during health and disease. Below is a list of immunology-related articles.

References

  1. ↑ Murphy PM, Baggiolini M, Charo IF, Hébert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, Power CA (2000). "International union of pharmacology. XXII. Nomenclature for chemokine receptors" (abstract page). Pharmacol. Rev. 52 (1): 145–76. PMID   10699158.
  2. ↑ Murphy PM (2002). "International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature". Pharmacol. Rev. 54 (2): 227–9. doi:10.1124/pr.54.2.227. PMID   12037138. S2CID   40063223.
  3. 1 2 Allen, Samantha J.; Crown, Susan E.; Handel, Tracy M. (2007-01-01). "Chemokine: receptor structure, interactions, and antagonism". Annual Review of Immunology. 25: 787–820. doi: 10.1146/annurev.immunol.24.021605.090529 . ISSN   0732-0582. PMID   17291188.
  4. 1 2 3 4 5 Kakinuma, Takashi; Hwang, Sam T. (2006-04-01). "Chemokines, chemokine receptors, and cancer metastasis". Journal of Leukocyte Biology. 79 (4): 639–651. doi: 10.1189/jlb.1105633 . ISSN   0741-5400. PMID   16478915.
  5. ↑ Arimont A, Sun S, Smit MJ, Leurs R, de Esch IJ, de Graaf C (2017). "Structural Analysis of Chemokine Receptor-Ligand Interactions". J Med Chem. 60 (12): 4735–4779. doi:10.1021/acs.jmedchem.6b01309. PMC   5483895 . PMID   28165741.
  6. 1 2 Murdoch C, Finn A (2000). "Chemokine receptors and their role in inflammation and infectious diseases". Blood. 95 (10): 3032–43. doi:10.1182/blood.V95.10.3032.010k17_3032_3043. PMID   10807766.
  7. 1 2 Murdoch, Craig; Finn, Adam (2000). "Chemokine receptors and their role in inflammation and infectious diseases". Blood. 95 (10): 3032–3043. doi:10.1182/blood.V95.10.3032.010k17_3032_3043. PMID   10807766.
  8. 1 2 3 4 5 6 Galvani, Alison P.; Slatkin, Montgomery (2003-12-09). "Evaluating plague and smallpox as historical selective pressures for the CCR5-Delta 32 HIV-resistance allele". Proceedings of the National Academy of Sciences of the United States of America. 100 (25): 15276–15279. Bibcode:2003PNAS..10015276G. doi: 10.1073/pnas.2435085100 . ISSN   0027-8424. PMC   299980 . PMID   14645720.
  9. ↑ Mecsas, Joan; Franklin, Greg; Kuziel, William A.; Brubaker, Robert R.; Falkow, Stanley; Mosier, Donald E. (2004-02-12). "Evolutionary genetics: CCR5 mutation and plague protection". Nature. 427 (6975): 606. Bibcode:2004Natur.427..606M. doi: 10.1038/427606a . ISSN   1476-4687. PMID   14961112. S2CID   4430235.
  10. ↑ Styer, Katie L.; Click, Eva M.; Hopkins, Gregory W.; Frothingham, Richard; Aballay, Alejandro (2007-07-01). "Study of the role of CCR5 in a mouse model of intranasal challenge with Yersinia pestis". Microbes and Infection / Institut Pasteur. 9 (9): 1135–1138. doi:10.1016/j.micinf.2007.04.012. ISSN   1286-4579. PMC   2754264 . PMID   17644454.
  11. ↑ Lalani, A. S.; Masters, J.; Zeng, W.; Barrett, J.; Pannu, R.; Everett, H.; Arendt, C. W.; McFadden, G. (1999-12-03). "Use of chemokine receptors by poxviruses". Science. 286 (5446): 1968–1971. doi:10.1126/science.286.5446.1968. ISSN   0036-8075. PMID   10583963.
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