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Chemokine receptor

January 20, 2023

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. Four families of chemokine receptors differ in spacing of cysteine residues near N-terminal of the receptor.[4]

Typical structure of a chemokine receptor, with seven transmembrane domains and a characteristic "DRY" motif in the second intracellular domain. Chemokine receptors are usually linked to a G-protein through which they signal.
Chemokine receptor family
Identifiers
SymbolChemokine_rcpt
InterProIPR000355

Structural characteristics

Chemokine receptors are G protein-coupled receptors containing 7 transmembrane domains [5] that are found predominantly on the surface of leukocytes, making it one of the rhodopsin-like receptors. 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 helical transmembrane domains 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

Further information: Heterotrimeric G protein

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)

Main article: CCR5-Δ32

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]

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. ^ a b 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. ^ a b c d e 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. ^ a b 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. ^ a b 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. ^ a b c d e f 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. 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. 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.

External links

  • "Chemokine Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.

January 20, 2023
chemokine, receptor, cytokine, receptors, found, surface, certain, cells, that, interact, with, type, cytokine, called, chemokine, there, have, been, distinct, chemokine, receptors, discovered, humans, each, rhodopsin, like, transmembrane, structure, couples, . 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 Four families of chemokine receptors differ in spacing of cysteine residues near N terminal of the receptor 4 Typical structure of a chemokine receptor with seven transmembrane domains and a characteristic DRY motif in the second intracellular domain Chemokine receptors are usually linked to a G protein through which they signal Chemokine receptor familyIdentifiersSymbolChemokine rcptInterProIPR000355 Contents 1 Structural characteristics 2 Signal transduction 3 Selective pressures on Chemokine receptor 5 CCR5 4 Families 5 References 6 External linksStructural characteristics EditChemokine receptors are G protein coupled receptors containing 7 transmembrane domains 5 that are found predominantly on the surface of leukocytes making it one of the rhodopsin like receptors 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 helical transmembrane domains 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 EditFurther information Heterotrimeric G protein 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 Ga 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 Ga 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 EditMain article CCR5 D32 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 D32 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 D32 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 D32 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 D32 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 D32 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 D32 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 D32 Families EditCXC chemokine receptors six members CC chemokine receptors ten eleven members C chemokine receptors one member XCR1 CX3C chemokine receptors one member CX3CR1 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 Edit Murphy PM Baggiolini M Charo IF Hebert 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 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 a b 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 a b c d e 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 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 a b 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 a b 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 a b c d e f 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 doi 10 1073 pnas 2435085100 ISSN 0027 8424 PMC 299980 PMID 14645720 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 doi 10 1038 427606a ISSN 1476 4687 PMID 14961112 S2CID 4430235 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 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 External links Edit Chemokine Receptors IUPHAR Database of Receptors and Ion Channels International Union of Basic and Clinical Pharmacology The Cytokine Receptor Database Retrieved from https en wikipedia org w index php title Chemokine receptor amp oldid 1076599625, wikipedia, wiki, book, books, library,

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