Journal of Molecular Evolution

, Volume 80, Issue 2, pp 130–141 | Cite as

Adaptive Evolution of Formyl Peptide Receptors in Mammals

  • Yoshinori MutoEmail author
  • Stéphane Guindon
  • Toshiaki Umemura
  • László Kőhidai
  • Hiroshi Ueda
Original Article


The formyl peptide receptors (FPRs) are a family of chemoattractant receptors with important roles in host defense and the regulation of inflammatory reactions. In humans, three FPR paralogs have been identified (FPR1, FPR2, and FPR3) and may have functionally diversified by gene duplication and adaptive evolution. However, the evolutionary mechanisms operating in the diversification of FPR family genes and the changes in selection pressures have not been characterized to date. Here, we have made a comprehensive evolutionary analysis of FPR genes from mammalian species. Phylogenetic analysis showed that an early duplication was responsible for FPR1 and FPR2/FPR3 splitting, and FPR3 originated from the latest duplication event near the origin of primates. Codon-based tests of positive selection reveal interesting patterns in FPR1 and FPR2 versus FPR3, with the first two genes showing clear evidence of positive selection at some sites while the majority of them evolve under strong negative selection. In contrast, our results suggest that the selective pressure may be relaxed in the FPR3 lineage. Of the six amino acid sites inferred to evolve under positive selection in FPR1 and FPR2, four sites were located in extracellular loops of the protein. The electrostatic potential of the extracellular surface of FPR might be affected more frequently with amino acid substitutions in positively selected sites. Thus, positive selection of FPRs among mammals may reflect a link between changes in the sequence and surface structure of the proteins and is likely to be important in the host’s defense against invading pathogens.


Molecular evolution Formyl peptide receptor Positive selection Mammal 


Conflict of interest

The authors declare that they have no conflict of interests.

Supplementary material

239_2015_9666_MOESM1_ESM.pdf (1.1 mb)
Supplementary material 1 (PDF 1151 kb)
239_2015_9666_MOESM2_ESM.pdf (262 kb)
Supplementary material 2 (PDF 262 kb)
239_2015_9666_MOESM3_ESM.pdf (285 kb)
Supplementary material 3 (PDF 284 kb)
239_2015_9666_MOESM4_ESM.docx (17 kb)
Supplementary material 4 (DOCX 17 kb)
239_2015_9666_MOESM5_ESM.docx (18 kb)
Supplementary material 5 (DOCX 17 kb)
239_2015_9666_MOESM6_ESM.docx (18 kb)
Supplementary material 6 (DOCX 17 kb)
239_2015_9666_MOESM7_ESM.docx (14 kb)
Supplementary material 7 (DOCX 14 kb)


  1. Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402PubMedCentralPubMedCrossRefGoogle Scholar
  2. Alvarez V, Coto E, Setien F, Gonzalez-Roces S, Lopez-Larrea C (1996) Molecular evolution of the N-formyl peptide and C5a receptors in non-human primates. Immunogenetics 44:446–452PubMedCrossRefGoogle Scholar
  3. Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA (2001) Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci USA 98:10037–10041. doi: 10.1073/pnas.181342398 PubMedCentralPubMedCrossRefGoogle Scholar
  4. Cui Y, Le Y, Yazawa H, Gong W, Wang JM (2002) Potential role of the formyl peptide receptor-like 1 (FPRL1) in inflammatory aspects of Alzheimer’s disease. J Leukoc Biol 72:628–635PubMedGoogle Scholar
  5. Darriba D, Taboada GL, Doallo R, Posada D (2012) jModelTest 2: more models, new heuristics and parallel computing. Nat Methods 9:772. doi: 10.1038/nmeth.2109 PubMedCrossRefGoogle Scholar
  6. de Paulis A et al (2004) Urokinase induces basophil chemotaxis through a urokinase receptor epitope that is an endogenous ligand for formyl peptide receptor-like 1 and -like 2. J Immunol 173:5739–5748PubMedCrossRefGoogle Scholar
  7. Edwards BS et al (2005) Integration of virtual screening with high-throughput flow cytometry to identify novel small molecule formylpeptide receptor antagonists. Mol Pharmacol 68:1301–1310. doi: 10.1124/mol.105.014068 PubMedCrossRefGoogle Scholar
  8. Endo T, Ikeo K, Gojobori T (1996) Large-scale search for genes on which positive selection may operate. Mol Biol Evol 13:685–690PubMedCrossRefGoogle Scholar
  9. Felsenstein J (1985) Confidence limits on phylogenies: an approach using the bootstrap. Evolution 39:783–791CrossRefGoogle Scholar
  10. Fredriksson R, Schioth HB (2005) The repertoire of G-protein-coupled receptors in fully sequenced genomes. Mol Pharmacol 67:1414–1425. doi: 10.1124/mol.104.009001 PubMedCrossRefGoogle Scholar
  11. Fredriksson R, Lagerstrom MC, Schioth HB (2005) Expansion of the superfamily of G-protein-coupled receptors in chordates. Ann N Y Acad Sci 1040:89–94. doi: 10.1196/annals.1327.011 PubMedCrossRefGoogle Scholar
  12. Fujita H, Kato T, Watanabe N, Takahashi T, Kitagawa S (2011) Stimulation of human formyl peptide receptors by calpain inhibitors: homology modeling of receptors and ligand docking simulation. Arch Biochem Biophys 516:121–127. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  13. Furlong RF, Yang Z (2008) Diversifying and purifying selection in the peptide binding region of DRB in mammals. J Mol Evol 66:384–394. doi: 10.1007/s00239-008-9092-6 PubMedCrossRefGoogle Scholar
  14. Gavins FN (2010) Are formyl peptide receptors novel targets for therapeutic intervention in ischaemia-reperfusion injury? Trends Pharmacol Sci 31:266–276. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  15. Graham GJ, McKimmie CS (2006) Chemokine scavenging by D6: a movable feast? Trends Immunol 27:381–386. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  16. Guindon S, Rodrigo AG, Dyer KA, Huelsenbeck JP (2004) Modeling the site-specific variation of selection patterns along lineages. Proc Natl Acad Sci USA 101:12957–12962. doi: 10.1073/pnas.0402177101 PubMedCentralPubMedCrossRefGoogle Scholar
  17. Guindon S, Dufayard JF, Lefort V, Anisimova M, Hordijk W, Gascuel O (2010) New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. Syst Biol 59:307–321. doi: 10.1093/sysbio/syq010 PubMedCrossRefGoogle Scholar
  18. Ha HS, Huh JW, Gim JA, Han K, Kim HS (2011) Transcriptional variations mediated by an alternative promoter of the FPR3 gene. Mamm Genome 22:621–633. doi: 10.1007/s00335-011-9341-7 PubMedCrossRefGoogle Scholar
  19. Hall TA (1999) BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symp Ser 41:95–98Google Scholar
  20. He HQ, Liao D, Wang ZG, Wang ZL, Zhou HC, Wang MW, Ye RD (2013) Functional characterization of three mouse formyl peptide receptors. Mol Pharmacol 83:389–398. doi: 10.1124/mol.112.081315 PubMedCentralPubMedCrossRefGoogle Scholar
  21. Katoh K, Toh H (2008) Recent developments in the MAFFT multiple sequence alignment program. Brief Bioinform 9:286–298. doi: 10.1093/bib/bbn013 PubMedCrossRefGoogle Scholar
  22. Khlebnikov AI, Schepetkin IA, Kirpotina LN, Brive L, Dahlgren C, Jutila MA, Quinn MT (2012) Molecular docking of 2-(benzimidazol-2-ylthio)-N-phenylacetamide-derived small-molecule agonists of human formyl peptide receptor 1. J Mol Model 18:2831–2843. doi: 10.1007/s00894-011-1307-x PubMedCentralPubMedCrossRefGoogle Scholar
  23. Kilby JM et al (1998) Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med 4:1302–1307. doi: 10.1038/3293 PubMedCrossRefGoogle Scholar
  24. Le Y, Murphy PM, Wang JM (2002) Formyl-peptide receptors revisited. Trends Immunol 23:541–548PubMedCrossRefGoogle Scholar
  25. Liberles SD et al (2009) Formyl peptide receptors are candidate chemosensory receptors in the vomeronasal organ. Proc Natl Acad Sci USA 106:9842–9847. doi: 10.1073/pnas.0904464106 PubMedCentralPubMedCrossRefGoogle Scholar
  26. Lu A, Guindon S (2013) Performance of standard and stochastic branch-site models for detecting positive selection among coding sequences. Mol Biol Evol 31:484–495. doi: 10.1093/molbev/mst198 PubMedCrossRefGoogle Scholar
  27. Migeotte I et al (2005) Identification and characterization of an endogenous chemotactic ligand specific for FPRL2. J Exp Med 201:83–93. doi: 10.1084/jem.20041277 PubMedCentralPubMedCrossRefGoogle Scholar
  28. Mills JS, Miettinen HM, Cummings D, Jesaitis AJ (2000) Characterization of the binding site on the formyl peptide receptor using three receptor mutants and analogs of Met-Leu-Phe and Met-Met-Trp-Leu-Leu. J Biol Chem 275:39012–39017. doi: 10.1074/jbc.M003081200 PubMedCrossRefGoogle Scholar
  29. Naumann U et al (2010) CXCR7 functions as a scavenger for CXCL12 and CXCL11. PLoS ONE 5:e9175. doi: 10.1371/journal.pone.0009175 PubMedCentralPubMedCrossRefGoogle Scholar
  30. Nielsen R, Yang Z (1998) Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene. Genetics 148:929–936PubMedCentralPubMedGoogle Scholar
  31. Prossnitz ER, Ye RD (1997) The N-formyl peptide receptor: a model for the study of chemoattractant receptor structure and function. Pharmacol Ther 74:73–102PubMedCrossRefGoogle Scholar
  32. Quehenberger O, Prossnitz ER, Cavanagh SL, Cochrane CG, Ye RD (1993) Multiple domains of the N-formyl peptide receptor are required for high-affinity ligand binding. Construction and analysis of chimeric N-formyl peptide receptors. J Biol Chem 268:18167–18175PubMedGoogle Scholar
  33. Rabiet MJ, Macari L, Dahlgren C, Boulay F (2011) 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. J Biol Chem 286:26718–26731. doi: 10.1074/jbc.M111.244590 PubMedCentralPubMedCrossRefGoogle Scholar
  34. Riviere S, Challet L, Fluegge D, Spehr M, Rodriguez I (2009) Formyl peptide receptor-like proteins are a novel family of vomeronasal chemosensors. Nature 459:574–577. doi: 10.1038/nature08029 PubMedCrossRefGoogle Scholar
  35. Rompler H, Staubert C, Thor D, Schulz A, Hofreiter M, Schoneberg T (2007) G protein-coupled time travel: evolutionary aspects of GPCR research. Mol Interv 7:17–25. doi: 10.1124/mi.7.1.5 PubMedCrossRefGoogle Scholar
  36. Roy A, Kucukural A, Zhang Y (2010) I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 5:725–738. doi: 10.1038/nprot.2010.5 PubMedCentralPubMedCrossRefGoogle Scholar
  37. Saitou N, Nei M (1987) The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 4:406–425PubMedGoogle Scholar
  38. Schiffmann E, Showell HV, Corcoran BA, Ward PA, Smith E, Becker EL (1975) The isolation and partial characterization of neutrophil chemotactic factors from Escherichia coli. J Immunol 114:1831–1837PubMedGoogle Scholar
  39. Schioth HB, Fredriksson R (2005) The GRAFS classification system of G-protein coupled receptors in comparative perspective. Gen Comp Endocrinol 142:94–101. doi: 10.1016/j.ygcen.2004.12.018 PubMedCrossRefGoogle Scholar
  40. Southgate EL, He RL, Gao JL, Murphy PM, Nanamori M, Ye RD (2008) Identification of formyl peptides from Listeria monocytogenes and Staphylococcus aureus as potent chemoattractants for mouse neutrophils. J Immunol 181:1429–1437PubMedCentralPubMedCrossRefGoogle Scholar
  41. Stabenau A, McVicker G, Melsopp C, Proctor G, Clamp M, Birney E (2004) The Ensembl core software libraries. Genome Res 14:929–933. doi: 10.1101/gr.1857204 PubMedCentralPubMedCrossRefGoogle Scholar
  42. Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S (2011) MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 28:2731–2739. doi: 10.1093/molbev/msr121 PubMedCentralPubMedCrossRefGoogle Scholar
  43. Tsuruki T, Takahata K, Yoshikawa M (2007) Mechanism of the protective effect of intraperitoneally administered agonists for formyl peptide receptors against chemotherapy-induced alopecia. Biosci Biotechnol Biochem 71:1198–1202PubMedCrossRefGoogle Scholar
  44. Wooding S (2011) Signatures of natural selection in a primate bitter taste receptor. J Mol Evol 73:257–265. doi: 10.1007/s00239-011-9481-0 PubMedCrossRefGoogle Scholar
  45. Yang Z (2007) PAML 4: phylogenetic analysis by maximum likelihood. Mol Biol Evol 24:1586–1591. doi: 10.1093/molbev/msm088 PubMedCrossRefGoogle Scholar
  46. Yang H, Shi P (2010) Molecular and evolutionary analyses of formyl peptide receptors suggest the absence of VNO-specific FPRs in primates. J Genet Genomics 37:771–778. doi: 10.1016/S1673-8527(09)60094-1 PubMedCrossRefGoogle Scholar
  47. Yang Z, Swanson WJ (2002) Codon-substitution models to detect adaptive evolution that account for heterogeneous selective pressures among site classes. Mol Biol Evol 19:49–57PubMedCrossRefGoogle Scholar
  48. Yang Z, Nielsen R, Goldman N, Pedersen AM (2000) Codon-substitution models for heterogeneous selection pressure at amino acid sites. Genetics 155:431–449PubMedCentralPubMedGoogle Scholar
  49. Yang Z, Wong WS, Nielsen R (2005) Bayes empirical bayes inference of amino acid sites under positive selection. Mol Biol Evol 22:1107–1118. doi: 10.1093/molbev/msi097 PubMedCrossRefGoogle Scholar
  50. Ye RD et al (2009) International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family. Pharmacol Rev 61:119–161. doi: 10.1124/pr.109.001578 PubMedCentralPubMedCrossRefGoogle Scholar
  51. Zhang Y (2008) I-TASSER server for protein 3D structure prediction. BMC Bioinform 9:40. doi: 10.1186/1471-2105-9-40 CrossRefGoogle Scholar
  52. Zhang ZD, Weinstock G, Gerstein M (2008) Rapid evolution by positive Darwinian selection in T-cell antigen CD4 in primates. J Mol Evol 66:446–456. doi: 10.1007/s00239-008-9097-1 PubMedCrossRefGoogle Scholar
  53. Zhou H, Zhou X, Kouadir M, Zhang Z, Yin X, Yang L, Zhao D (2009) Induction of macrophage migration by neurotoxic prion protein fragment. J Neurosci Methods 181:1–5. doi: 10.1016/j.jneumeth.2009.04.002 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Yoshinori Muto
    • 1
    • 2
    Email author
  • Stéphane Guindon
    • 3
  • Toshiaki Umemura
    • 4
  • László Kőhidai
    • 5
  • Hiroshi Ueda
    • 1
    • 6
  1. 1.United Graduate School of Drug Discovery and Medical Information SciencesGifu UniversityGifuJapan
  2. 2.Department of Functional BioscienceGifu University School of MedicineGifuJapan
  3. 3.Department of StatisticsThe University of AucklandAucklandNew Zealand
  4. 4.Graduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
  5. 5.Department of Genetics, Cell and ImmunobiologySemmelweis UniversityBudapestHungary
  6. 6.Department of Biomolecular Science, Faculty of EngineeringGifu UniversityGifuJapan

Personalised recommendations