Biology:Formyl peptide receptor 3

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

N-formyl peptide receptor 3 (FPR3) is a receptor protein that in humans is encoded by the FPR3 gene.[1][2][3]

Nomenclature note

Confusingly, there are two nomenclatures for FPR receptors and their genes, the first one used, FPR, FPR1, and FPR2 and its replacement (which corresponds directly to these three respective receptors and their genes), FPR1, FPR2, and FPR3. The latter nomenclature is recommended by the International Union of Basic and Clinical Pharmacology[4] and is used here. Other previously used names for FPR1 are NFPR, and FMLPR; for FPR2 are FPRH1, FPRL1, RFP, LXA4R, ALXR, FPR2/ALX, HM63, FMLPX, and FPR2A; and for FPR3 are FPRH2, FPRL2, and FMLPY.[4]

FPR3 function

The overall function of FPR3 is quite unclear. Compared to FPR1 and FPR2, FPR3 is highly phosphorylated (a signal for receptor inactivation and internalization) and more localized to small intracellular vesicles. This suggests that FPR3 rapidly internalizes after binding its ligands and thereby may serve as a "decoy" receptor to reduce the binding of its ligands to FRP1 and FRP2 receptors.[5][6]

Genes

Humans

The FPR3 gene was cloned and named based on the similarity of the amino acid sequence which it encodes to that encoded by the gene for FPR1 (see formyl peptide receptor 1 for details)[7][8][9][10][11][12][13][14] The studies indicated that FPR3 is composed of 352 amino acids and its gene, similar to FPR1, has an intronless open reading frames which encodes a protein with the 7 transmembrane structure of G protein coupled receptors; FPR3 has 69% and 72% amino acid sequence identities with FPR1.[4] All three genes localize to chromosome 19q.13.3 in the order of FPR1 (19q13.410), FPR2 (19q13.3-q13.4), and FPR3 (19q13.3-q13.4) to form a cluster which also includes the genes for another G protein-coupled chemotactic factor receptor, the C5a receptor (also termed CD88) and GPR77, and a second C5a receptor, C5a2 (C5L2), which has the structure of a G protein coupled receptor but fails to couple to G proteins and is of debated function.[15]

Mice

Mouse FPR receptors localize to chromosome 17A3.2 in the following order: Fpr1, Fpr-rs2 (or fpr2), Fpr-rs1 (or LXA4R), Fpr-rs4, Fpr-rs7, Fpr-rs7, Fpr-rs6, and Fpr-rs3; Pseudogenes ψFpr-rs2 and ψFpr-rs3 (or ψFpr-rs5) lie just after Fpr-rs2 and Fpr-rs1, respectively. All of the active mouse FPR receptors have ≥50% amino acid sequence identity with each other as well as with the three human FPR receptors.[16] Based on its predominantly intracellular distribution, mFpr-rs1 correlates, and therefore may share functionality, with human FPR3;[17][18][19] However, the large number of mouse compared to human FPR receptors makes it difficult to extrapolate human FPR functions based on genetic (e.g. gene knockout or forced overexpression) or other experimental manipulations of the FPR receptors in mice.

Other species

FPR receptors are widely distributed throughout mammalian species with the FPR1, FPR2, and FPR3 paralogs, based on phylogenetic analysis, originating from a common ancestor and early duplication of FPR1 and FPR2/FPR3 splitting with FPR3 originating from the latest duplication event near the origin of primates.[20] Rabbits express an ortholog of FPR1 (78% amino acid sequence identity) with high binding affinity for FMLP; rats express an ortholog of FPR2 (74% amino acid sequence identity) with high affinity for lipoxin A4.[16]

Cellular and tissue distribution

FPL3 is expressed by circulating monocytes, eosinophils, and basophils but not neutrophils; tissue macrophages and dendritic cells.[16][21][22]

Ligands and potential ligand-based disease related activities

The functions of FPR3 and the few ligands which activate it have not been fully clarified. Despite its homology to FPR1, FPR3 is unresponsive to many FPR1-stimulating formyl peptides including FMLP. However, fMMYALF, a N-formyl hexapeptide derived from the mitochondrial protein, NADH dehydrogenase subunit 6, is a weak agonist for FPR3 but >100-fold more potent in stimulating FPR1 and FPR2.[23] F2L is a naturally occurring acylated peptide derived from the N-terminal sequence of heme-binding protein 1 by cathepsin D cleavage that potently stimulates chemotaxis through FPR3 in monocytes and monocyte-derived dendritic cells.[24] F2L thereby may be a pro-inflammatory stimulus for FPR3.[6] Similar to FPR2 (see FPR2 section), FPR3 is activated by humanin and thereby may be involved in inhibiting the inflammation occurring in and perhaps contributing to Alzheimer's disease.[25]

See also

References

  1. ↑ "Mapping of genes for the human C5a receptor (C5AR), human FMLP receptor (FPR), and two FMLP receptor homologue orphan receptors (FPRH1, FPRH2) to chromosome 19". Genomics 13 (2): 437–40. Jun 1992. doi:10.1016/0888-7543(92)90265-T. PMID 1612600. 
  2. ↑ "Differential expression of members of the N-formylpeptide receptor gene cluster in human phagocytes". Biochemical and Biophysical Research Communications 201 (1): 174–9. May 1994. doi:10.1006/bbrc.1994.1685. PMID 8198572. 
  3. ↑ "Entrez Gene: FPRL2 formyl peptide receptor-like 2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2359. 
  4. ↑ 4.0 4.1 4.2 "International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family". Pharmacological Reviews 61 (2): 119–61. Jun 2009. doi:10.1124/pr.109.001578. PMID 19498085. 
  5. ↑ "N-formyl peptide receptor 3 (FPR3) departs from the homologous FPR2/ALX receptor with regard to the major processes governing chemoattractant receptor regulation, expression at the cell surface, and phosphorylation". The Journal of Biological Chemistry 286 (30): 26718–31. Jul 2011. doi:10.1074/jbc.M111.244590. PMID 21543323. 
  6. ↑ 6.0 6.1 "The Role of Formylated Peptides and Formyl Peptide Receptor 1 in Governing Neutrophil Function during Acute Inflammation". The American Journal of Pathology 185 (5): 1172–1184. May 2015. doi:10.1016/j.ajpath.2015.01.020. PMID 25791526. 
  7. ↑ "Synthesis and use of a novel N-formyl peptide derivative to isolate a human N-formyl peptide receptor cDNA". Biochemical and Biophysical Research Communications 168 (3): 1103–9. May 1990. doi:10.1016/0006-291x(90)91143-g. PMID 2161213. 
  8. ↑ "The human N-formylpeptide receptor. Characterization of two cDNA isolates and evidence for a new subfamily of G-protein-coupled receptors". Biochemistry 29 (50): 11123–33. Dec 1990. doi:10.1021/bi00502a016. PMID 2176894. 
  9. ↑ "The formyl peptide chemoattractant receptor is encoded by a 2 kilobase messenger RNA. Expression in Xenopus oocytes". FEBS Letters 261 (2): 353–7. Feb 1990. doi:10.1016/0014-5793(90)80590-f. PMID 1690150. 
  10. ↑ "Functional reconstitution of fMet-Leu-Phe receptor in Xenopus laevis oocytes". The Journal of Biological Chemistry 265 (11): 5964–6. Apr 1990. doi:10.1016/S0021-9258(19)39276-2. PMID 2156834. 
  11. ↑ "Cloning of the gene coding for a human receptor for formyl peptides. Characterization of a promoter region and evidence for polymorphic expression". Biochemistry 31 (46): 11595–9. Nov 1992. doi:10.1021/bi00161a044. PMID 1445895. 
  12. ↑ "Mapping of genes for the human C5a receptor (C5AR), human FMLP receptor (FPR), and two FMLP receptor homologue orphan receptors (FPRH1, FPRH2) to chromosome 19". Genomics 13 (2): 437–40. Jun 1992. doi:10.1016/0888-7543(92)90265-t. PMID 1612600. 
  13. ↑ "A structural homologue of the N-formyl peptide receptor. Characterization and chromosome mapping of a peptide chemoattractant receptor family". The Journal of Biological Chemistry 267 (11): 7637–43. Apr 1992. doi:10.1016/S0021-9258(18)42563-X. PMID 1373134. 
  14. ↑ "Isolation of a cDNA that encodes a novel granulocyte N-formyl peptide receptor". Biochemical and Biophysical Research Communications 184 (2): 582–9. Apr 1992. doi:10.1016/0006-291x(92)90629-y. PMID 1374236. 
  15. ↑ "C5L2: a controversial receptor of complement anaphylatoxin, C5a". FASEB Journal 27 (3): 855–64. Mar 2013. doi:10.1096/fj.12-220509. PMID 23239822. 
  16. ↑ 16.0 16.1 16.2 "Formyl peptide receptors: a promiscuous subfamily of G protein-coupled receptors controlling immune responses". Cytokine & Growth Factor Reviews 17 (6): 501–19. Dec 2006. doi:10.1016/j.cytogfr.2006.09.009. PMID 17084101. 
  17. ↑ "Functional characterization of three mouse formyl peptide receptors". Molecular Pharmacology 83 (2): 389–98. Feb 2013. doi:10.1124/mol.112.081315. PMID 23160941. 
  18. ↑ "Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors". The Journal of Experimental Medicine 185 (9): 1693–704. May 1997. doi:10.1084/jem.185.9.1693. PMID 9151906. 
  19. ↑ "Identification, cloning, and functional characterization of a murine lipoxin A4 receptor homologue gene". Journal of Immunology 169 (6): 3363–9. Sep 2002. doi:10.4049/jimmunol.169.6.3363. PMID 12218158. 
  20. ↑ "Adaptive evolution of formyl peptide receptors in mammals". Journal of Molecular Evolution 80 (2): 130–41. Feb 2015. doi:10.1007/s00239-015-9666-z. PMID 25627928. Bibcode: 2015JMolE..80..130M. 
  21. ↑ "Basophils infiltrate human gastric mucosa at sites of Helicobacter pylori infection, and exhibit chemotaxis in response to H. pylori-derived peptide Hp(2-20)". Journal of Immunology 172 (12): 7734–43. Jun 2004. doi:10.4049/jimmunol.172.12.7734. PMID 15187157. 
  22. ↑ "Adrenergic modulation of migration, CD11b and CD18 expression, ROS and interleukin-8 production by human polymorphonuclear leukocytes". Inflammation Research 64 (2): 127–35. Feb 2015. doi:10.1007/s00011-014-0791-8. PMID 25561369. 
  23. ↑ "Human mitochondria-derived N-formylated peptides are novel agonists equally active on FPR and FPRL1, while Listeria monocytogenes-derived peptides preferentially activate FPR". European Journal of Immunology 35 (8): 2486–95. Aug 2005. doi:10.1002/eji.200526338. PMID 16025565. 
  24. ↑ "Identification and characterization of an endogenous chemotactic ligand specific for FPRL2". The Journal of Experimental Medicine 201 (1): 83–93. Jan 2005. doi:10.1084/jem.20041277. PMID 15623572. 
  25. ↑ "N-Formylated humanin activates both formyl peptide receptor-like 1 and 2". Biochemical and Biophysical Research Communications 324 (1): 255–61. Nov 2004. doi:10.1016/j.bbrc.2004.09.046. PMID 15465011. 

Further reading

  • "The synthetic peptide Trp-Lys-Tyr-Met-Val-Met-NH2 specifically activates neutrophils through FPRL1/lipoxin A4 receptors and is an agonist for the orphan monocyte-expressed chemoattractant receptor FPRL2". The Journal of Biological Chemistry 276 (24): 21585–93. Jun 2001. doi:10.1074/jbc.M007769200. PMID 11285256. 
  • "Human dendritic cells express functional formyl peptide receptor-like-2 (FPRL2) throughout maturation". Journal of Leukocyte Biology 72 (3): 598–607. Sep 2002. doi:10.1189/jlb.72.3.598. PMID 12223529. 
  • "Phagocyte activation by Trp-Lys-Tyr-Met-Val-Met, acting through FPRL1/LXA4R, is not affected by lipoxin A4". Scandinavian Journal of Immunology 56 (5): 470–6. Nov 2002. doi:10.1046/j.1365-3083.2002.01149.x. PMID 12410796. 
  • "An annexin 1 N-terminal peptide activates leukocytes by triggering different members of the formyl peptide receptor family". Journal of Immunology 172 (12): 7669–76. Jun 2004. doi:10.4049/jimmunol.172.12.7669. PMID 15187149. 
  • "N-Formylated humanin activates both formyl peptide receptor-like 1 and 2". Biochemical and Biophysical Research Communications 324 (1): 255–61. Nov 2004. doi:10.1016/j.bbrc.2004.09.046. PMID 15465011. 
  • "The synthetic peptide Trp-Lys-Tyr-Met-Val-D-Met inhibits human monocyte-derived dendritic cell maturation via formyl peptide receptor and formyl peptide receptor-like 2". Journal of Immunology 175 (2): 685–92. Jul 2005. doi:10.4049/jimmunol.175.2.685. PMID 16002663. 
  • "F2L, a peptide derived from heme-binding protein, inhibits formyl peptide receptor-mediated signaling". Biochemical and Biophysical Research Communications 359 (4): 985–90. Aug 2007. doi:10.1016/j.bbrc.2007.06.001. PMID 17577578. 

External links



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