Wikipedia

Chemokine receptor

Chemokine receptorsarecytokine receptorsfound on the surface of certain cells that interact with a type ofcytokinecalled achemokine.[1][2]There have been 20 distinct chemokine receptors discovered in humans.[3]Each has arhodopsin-like7-transmembrane(7TM) structure and couples toG-proteinforsignal transductionwithin a cell, making them members of a large protein family ofG protein-coupled receptors.Following interaction with their specific chemokineligands,chemokine receptors trigger afluxinintracellularcalcium (Ca2+) ions (calcium signaling). This causes cell responses, including the onset of a process known aschemotaxisthat 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 receptorsandXC chemokine receptorsthat 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]

Typical structure of achemokine receptor,with seven transmembrane helices and a characteristic "DRY" motif in the second intracellular loop. Chemokine receptors are usually linked to aG-proteinthrough which they signal.
Chemokine receptor family
Identifiers
SymbolChemokine_rcpt
InterProIPR000355

Structural characteristics

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Chemokine receptors areG protein-coupled receptorscontaining 7transmembranehelices[5]that are found predominantly on the surface ofleukocytes.Approximately 19 different chemokine receptors have been characterized to date, which share many common structural features. They are composed of about 350amino acidsthat are divided into a short and acidic N-terminal end, seven transmembrane helices with threeintracellularand threeextracellularhydrophilicloops, and an intracellular C-terminus containingserineandthreonineresidues that act asphosphorylationsites during receptor regulation. The first two extracellular loops of chemokine receptors are linked together bydisulfide bondingbetween two conservedcysteineresidues. TheN-terminalend of a chemokine receptor binds to chemokines and is important for ligand specificity.G-proteinscouple 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

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Further information:Heterotrimeric G protein

Intracellular signalingby chemokine receptors is dependent on neighbouring G-proteins. G-proteins exist as a heterotrimer; they are composed of three distinct subunits. When the moleculeGDPis 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 calledGTP,and the dissociation of the different G protein subunits. The subunit called Gα activates anenzymeknown asPhospholipase C(PLC) that is associated with thecell membrane.PLC cleavesPhosphatidylinositol (4,5)-bisphosphate(PIP2) to form twosecond messengermolecules calledinositol triphosphate(IP3) anddiacylglycerol(DAG); DAG activates another enzyme calledprotein kinase C(PKC), and IP3 triggers the release ofcalciumfrom intracellular stores. These events promote many signaling cascades, effecting a cellular response.[7]

For example, when CXCL8 (IL-8) binds to its specific receptors,CXCR1orCXCR2,a rise in intracellular calcium activates the enzymephospholipase D(PLD) that goes on to initiate an intracellular signaling cascade called theMAP kinase pathway.At the same time, the G-protein subunit Gα directly activates an enzyme calledprotein tyrosine kinase(PTK), which phosphorylatesserineandthreonineresidues in the tail of the chemokine receptor, causing its desensitisation or inactivation.[7]The initiatedMAP kinasepathway activates specific cellular mechanisms involved inchemotaxis,degranulation,release ofsuperoxideanions, and changes in the avidity ofcell adhesion moleculescalledintegrins.[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)

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Main article:CCR5-Δ32

Human Immunodeficiency virususes CCR5 receptor to target and infect hostT-cellsin 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 EuropeanCaucasianpopulation, 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:plagueandsmallpox.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 theYersinia pestis,which is the causative agent for plague. Manyin vivomouse studies have refuted this claim by showing no protective effects of CCR5-Δ32 allele in mice infected withY. 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]Assmallpoxhas 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.Myxomaandvariola majorbelong to the same family of viruses and myxoma has been shown to useCCR5receptor to enter its host.[11]Moreover,Yersiniais 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

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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]

References

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  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.PMID10699158.
  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.PMID12037138.S2CID40063223.
  3. ^abAllen, 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.ISSN0732-0582.PMID17291188.
  4. ^abcdeKakinuma, 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.ISSN0741-5400.PMID16478915.
  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.PMC5483895.PMID28165741.
  6. ^abMurdoch 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.PMID10807766.
  7. ^abMurdoch, 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.PMID10807766.
  8. ^abcdefGalvani, 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.ISSN0027-8424.PMC299980.PMID14645720.
  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.ISSN1476-4687.PMID14961112.S2CID4430235.
  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.ISSN1286-4579.PMC2754264.PMID17644454.
  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.ISSN0036-8075.PMID10583963.
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