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Evolutionary relationships among G protein-coupled receptors using a clustered database approach

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Abstract

Guanine nucleotide-binding proteincoupled receptors (GPCRs) comprise large and diverse gene families in fungi, plants, and the animal kingdom. GPCRs appear to share a common structure with 7 transmembrane segments, but sequence similarity is minimal among the most distant GPCRs. To reevaluate the question of evolutionary relationships among the disparate GPCR families, this study takes advantage of the dramatically increased number of cloned GPCRs. Sequences were selected from the National Center for Biotechnology Information (NCBI) nonredundant peptide database using iterative BLAST (Basic Local Alignment Search Tool) searches to yield a database of ∼1700 GPCRs and unrelated membrane proteins as controls, divided into 34 distinet clusters. For each cluster, separate position-specific matrices were established to optimize sequence comparisons among GPCRs. This approach resulted in significant alignments between distant GPCR families, including receptors for the biogenic amine/peptide, VIP/secretin, cAMP, STE3/MAP3 fungal pheromones, latrophilin, developmental receptors frizzled and smoothened, as well as the more distant metabotrobic glutamate receptors, the STE2/MAM2 fungal pheromone receptors, and GPR1, a fungal glucose receptor. On the other hand, alignment scores between these recognized GPCR clades with p40 (putative GPCR) and pml (putative GPCR), as well as bacteriorhodopsins, failed to support a finding of homology. This study provides a refined view of GPCR ancestry and serves as a reference database with hyperlinks to other sources. Moreover, it may facilitate database annotation and the assignment of orphan receptors to GPCR families.

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References

  1. Riek RP, Handschumacher MD, Sung SS, et al. Evolutionary conservation of both the hydrophilic and hydrophobic nature of transmembrane residues. J Theor Biol. 1995;172(3):245–258.

    Article  CAS  PubMed  Google Scholar 

  2. Kolakowski LF Jr. GPCRDb: a G-protein-coupled receptor database. Receptors Channels. 1994;2:1–7.

    CAS  PubMed  Google Scholar 

  3. Horn F, Weare J, Beukers MW, et al. GPCRDB: an, information system for G protein coupled receptors. Nucleic Acids Res. 1998;26:275–279.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Bargmann CI. Oltactory receptors, vomeronasal receptors, and the organization of olfactory information. Cell. 1997;90(4):585–587.

    Article  CAS  PubMed  Google Scholar 

  5. Slusarski DC, Corces VG, Moon RT. Interaction of Wnt and a frizzled homologue triggers G-protein-linked phosphatidylinositol signalling. Nature. 1997;390(6658):410–413.

    Article  CAS  PubMed  Google Scholar 

  6. Barnes MR, Duckworth DM, Beeley LJ. Frizzled proteins constitute a novel family of G protein-coupled receptors, most closely related to the Secretin family. Trends Pharmacol Sci. 1998;19(10):399–400.

    Article  CAS  PubMed  Google Scholar 

  7. Robertson HM. Two large families of chemoreceptor genes in the nematodes Caenorhabditis elegans and Caenorhabditis briggsae reveal extensive gene duplication. diversification, movement, and intron loss. Genome Res. 1998;8(5):449–463.

    CAS  PubMed  Google Scholar 

  8. Sugita S, Ichtchenko K, Khvotchev M, SYdhof TC. Alpha-latrotoxin receptor CIRL/latrophilin 1 (CL1) defines an unusual family of ubiquitous G-protein-linked receptors: G-protein coupling not required for triggering exocytosis. J Biol Chem. 1998;273(49):32715–32724.

    Article  CAS  PubMed  Google Scholar 

  9. Bockaert J, Pin JP. Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J. 1998;18(7):1723–1729.

    Article  Google Scholar 

  10. Wang D, SadŽe W, Quillan JM. Calmodulin binding to G protein-coupling domain of opioid receptors. J Biol Chem. 1999;274:22081–22088.

    Article  CAS  PubMed  Google Scholar 

  11. Rees DC, DeAntonio L, Eisenberg D. Hydrophobic organization of membrane proteins. Science. 1989;245(491):510–513.

    Article  CAS  PubMed  Google Scholar 

  12. Persson B, Argos P. Prediction of transmembrane segments in proteins utilising multiple sequence alignments. J Mol Biol. 1994;237(2):182–192.

    Article  CAS  PubMed  Google Scholar 

  13. Persson B, Argos P. Prediction of membrane protein topology utilizing multiple sequence alignments J Protein Chem. 1997;16(5):453–457.

    Article  CAS  PubMed  Google Scholar 

  14. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990;215(3):403–410.

    Article  CAS  PubMed  Google Scholar 

  15. Madden TL, Tatusov RL, Zhang J. Applications of network BLAST server. Methods Enzymol. 1996;266:131–141.

    Article  CAS  PubMed  Google Scholar 

  16. Altschul SF, Madden TL, SchŠffer AA, et al. Gapped BLAST and PSIBLAST a new generation of protein database search programs. Nucleic Acids Res. 1997;25(17):3389–3402.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Josefsson LG. Evidence for kinship between diverse G-protein coupled receptors. Gene. 1999;239(2):333–340.

    Article  CAS  PubMed  Google Scholar 

  18. Graul RC, SadŻe W. Evolutionary relationships among proteins probed by an iterative neighborhood cluster analysis (INCA): alignment of bacteriorhodopsins with the yeast sequence YRO2. Pharm Res. 1997;14(11);1533–1541.

    Article  CAS  PubMed  Google Scholar 

  19. Eddy SR. Multiple alignments and sequence searches. Trends Guide to Bioinformatics. Elsevier Science. Trends Supplement; 15–18.

  20. SchŠffer AA, Wolf YI, Ponting CP, Koonin EV, Aravind L, Altschul SF. IMPALA: matching a protein sequence against a collection of PSI-BLAST-constructed position-specific score matrices. Bioinformatics. 1999;15(12):1000–1011.

    Article  Google Scholar 

  21. Durbin R, Eddy S, Krogh A, Mitchison G. Biological Sequence Analysis: Probabilistic Models of Proteins and Nucleic Acids. Cambridge University Press; 1998.

  22. Bateman A, Birney E, Durbin R, Eddy SR, Howe KL, Sonnhammer EL. The Pfam protein families database. Nucleic Acids Res. 2000;28(1):263–266.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Kobilka BK, Frielle T, Collins S, et al. An intronless gene encoding a potential member of the family of receptors coupled to guanine nucleotide regulatory proteins. Nature. 1987;329(6134):75–79.

    Article  CAS  PubMed  Google Scholar 

  24. Olde B, McCombie WR. Molecular cloning and functional expression of a serotonin receptor from Caenorhabditis elegans. J Mol Neurosci. 1997;8(1):53–62.

    Article  CAS  PubMed  Google Scholar 

  25. Dunn RJ, Hackett NR, Huang KS, et al. Studies on the light-transducing pigment bacteriorhodopsin. Cold Spring, Harb Symp Quant Biol 1983;48(Pt2):853–862.

    Article  CAS  Google Scholar 

  26. Hart AC, KrŠmer H, Van Vactor DLJ, Paidhungat M, Zipursky SL. Induction of cell fate in the Drosophila retina: the bride of sevenless protein is predicted to contain a large extracellular domain and seven transmembrane segments. Genes Dev. 1990;4(11):1835–1847.

    Article  CAS  PubMed  Google Scholar 

  27. Klein PS, Sun TJ, Saxe CL 3rd, Kimmel AR, Johnson RL, Devreotes PN. A chemoattractant receptor controls development in Dictyostelium discoideum. Science. 1988;241(4872):1467–1472.

    Article  CAS  PubMed  Google Scholar 

  28. Lewis MJ, Pelham HR. A human homologne of the yeast HDEL receptor. Nature. 1990;348(6297):162–163.

    Article  CAS  PubMed  Google Scholar 

  29. Vinson CR, Conover S, Adler PN. A Drosophila tissue polarity locus encodes a protein containing seven potential transmembrane domains. Nature. 1989;338(6212)263–264.

    Article  CAS  PubMed  Google Scholar 

  30. Alcedo J, Ayzenzon M, Von Ohlen T, Noll M, Hooper JE. The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal. Cell. 1996;86(2):221–232.

    Article  CAS  PubMed  Google Scholar 

  31. Clark JA, Mezey E, Lam AS, Bonner TI. Distribution of the GABAB receptor subunit gb2 in rat CNS. Brain Res. 2000;860(1–2):41–52.

    Article  CAS  PubMed  Google Scholar 

  32. Yun CW, Tamaki H, Nakayama R, Yamamoto K, Kumagai H. Gprotein coupled receptor from yeast Saccharomyces cerevisiae. Biochem Biophys Res Commun. 1997;240(2):287–292.

    Article  CAS  PubMed  Google Scholar 

  33. Kraakman L, Lemaire K, Ma P, et al., A Saccharomyces cerevisiae G-protein coupled receptor, Gprl, is specifically required for glucose activation of the cAMP pathway during the transition to growth on glucose. Mol Microbiol. 1999;32(5):1002–1012.

    Article  CAS  PubMed  Google Scholar 

  34. White GR, Varley JM, Heighway J Isolation and characterization of a human homologue of the latrophilin gene from a region of 1p31.1 implicated in breast cancer. Oncogene. 1998;17(26):3513–3519.

    Article  CAS  PubMed  Google Scholar 

  35. Abe T, Tanemoto M, Nishio T, Hebert SC (unpublished). Metabotropic glutamate-like sequence in C. elegans.

  36. Desai MA, Burnett JP, Mayne NG, Schoepp DD. Cloning and expression of a human metabotropic glutamate receptor 1 alpha: enhanced coupling on co-transfection with a glutamate transporter. Mol Pharmacol. 1995;48(4):648–657.

    CAS  PubMed  Google Scholar 

  37. Bassi MT, Schiaffino MV, Renieri A, et al. Cloning of the gene for ocular albinism type 1 from the distal short arm of the X chromosome. Nature Gen. 1995;10(1):13–19.

    Article  CAS  Google Scholar 

  38. Sengupta P, Chou JH, Bargmann CI. odr-10 encodes a seven transmembrane domain olfactory receptor required for responses to the odorant diacetyl. Cell. 1996;84(6):899–909.

    Article  CAS  PubMed  Google Scholar 

  39. Buck L, Axel R A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell. 1991;65(1):175–187.

    Article  CAS  PubMed  Google Scholar 

  40. Mayer H, Salzer U, Breuss J, Ziegler S, Marchler-Bauer A, Prohaska R. Isolation molecular characterization, and tissue-specific expression of a novel putative G protein-coupled receptor. Biochim Biophys Acta. 1998;1395(3):301–308.

    Article  CAS  PubMed  Google Scholar 

  41. Murphy PM, Malech HL. Nucleotide sequence of a cDNA encoding a protein with primary structural similarity to G-protein coupled receptors. Nucleic Acids Res. 1990;18(7):1896.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Hooper JE, Scott MP. The Drosophila patched, gene encodes a putative membrane protein required for segmental patterning. Cell. 1989;59(4):751–765.

    Article  CAS  PubMed  Google Scholar 

  43. Regan JW, Bailey TJ, Pepperl DJ, et al. Cloning of a novel human prostaglandin receptor with characteristics of the pharmacologically defined EP2 subtype. Mol Pharmacol. 1994;46(2):213–220.

    CAS  PubMed  Google Scholar 

  44. Liang R, Fei YJ, Prasad PD, et al. Human intestinal H+/peptide cotransporter: cloning functional expression, and chromosomal localization. J Biol Chem. 1995;270(12):6456–6463.

    Article  CAS  PubMed  Google Scholar 

  45. Sherrington R, Rogaev EI, Liang Y, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimeras disease. Nature. 1995;375(6534):754–760.

    Article  CAS  PubMed  Google Scholar 

  46. Cheng Y, Lotan R Molecular cloning and characterization of a novel retmoic acid-inducible gene that encodes a putative G protein-coupled receptor. J Biol Chem. 1998;273(52):35008–35015.

    Article  CAS  PubMed  Google Scholar 

  47. Troemel ER, Chou JH, Dwyer ND, Colbert HA, Bargmann CI. Divergent seven transmembrane receptors are candidate chemosensory receptors in C. elegans Cell. 1995;83(2):207–218.

    Article  CAS  PubMed  Google Scholar 

  48. Burkholder AC, Hartwell LH. The yeast alpha-factor receptor: structural properties deduced from the sequence of the STE2 gene. Nucleic Acids Res. 1985;13(23):8463–8475.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Kitamura K, Shimoda C. The Schizosaccharomyces pombe MAM2 gene encodes a putative pheromone receptor which has a significant homology with the Saccharomyces cerevisiae STE2 protein. EMBO J. 1991;10(12):3743–3751.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Hagen DC, McCaffrey G, Sprague GF Jr. Evidence the yeast STE3 gene encodes a receptor for the peptide pheromone a factor gene sequence and implications for the structure of the presumed receptor. Proc Natl Acad Sci USA. 1986;83(5):1418–1422.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Tanaka K, Davey J, Imai Y, Yamamoto M. Schizosaccharomyces pombe map3+ encodes the putative M-factor receptor. Mol Cell Biol. 1993;13(1):80–88.

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Sreedharan SP, Patel DR, Huang JX, Goetzl EJ. Cloning and functional expression of a human neuroendocrine vasoactive intestinal peptide receptor. Biochem Biophys Res Commun. 1993;193(2):546–553.

    Article  CAS  PubMed  Google Scholar 

  53. Dulac C, Axel R A novel family of genes encoding putative pheromone receptors in mammals. Cell. 1995;83(2):195–206.

    Article  CAS  PubMed  Google Scholar 

  54. Feldmann H, Aigle M, Aljinovic G, et al. Complete DNA sequence of yeast chromosome II. EMBO J. 1994;13(24):5795–5809.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Aljinovic G, Pohl TM. Sequence and analysis of 24 kb on chromosome II of Saccharomyces cerevisiae Yeast. 1995;11(5):475–479.

    Article  CAS  PubMed  Google Scholar 

  56. Bieszke JA, Braun EL, Bean LE, Kang S, Natvig DO, Borkovich KA. The nop-1 gene of Neurospora crassa encodes a seven transmembrane helix retinal-binding protein homologous to archaeal thodopsins. Proc Natl Acad Sci USA. 1999;96(14):8034–8039.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Tusn‡dy GE, Simon I. Principles governing amino acid composition of integral membrane proteins: application to topology prediction. J Mol Biol. 1998;283(2):489–506.

    Article  Google Scholar 

  58. Brenner SE, Chothia C, Hubbard TJP. Assessing sequence comparison methods with reliable structurally identified distant evolutionary relationship. Proc Natl Acad Sci USA. 1998;95:6073–6078.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Retief JD. Phylogenetic analysis using PHYLIP. Methods Mol Biol. 2000;132:243–258.

    CAS  PubMed  Google Scholar 

  60. Felder CB. Gratil RC, Lee AY, Merkle H-P, SadŽe W. The venus flytrap of periplasmic binding proteins an ancient protein module present in multiple drug receptors PharmSci. 1999;1(2)http://www.pharmsci.org/journal/.

  61. Engelke G, Gutowski-Eckel Z, Hammelmann M, Entian KD. Biosynthesis of the lantibiotic nisin genomic organization and membrane localization of the NisB protein. Appl Environ Microbiol. 1992;58(11):3730–3743.

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Park J, Karplus K, Barrett C, et al. Sequence comparisons using multiple sequences detect three times as many remote homologues as pairwise methods. J Mol Biol. 1998;284:1201–1210.

    Article  CAS  PubMed  Google Scholar 

  63. Bauer H, Mayer H, Marchler-Bauer A, Salzer U, Prohaska R. Characterization of p40/GPR69A as a peripheral membrane protein related to the lantibiotic synthetase component C. Biochem Biophys Res Commun. 2000;275(1):69–74.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Incyte Genomics, 94304, Palo Alto, CA

    Richard C. Graul

  2. Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, University of California San Francisco, 94143, San Francisco, CA

    Wolfgang Sadée

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  1. Richard C. Graul
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  2. Wolfgang Sadée
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Correspondence to Wolfgang Sadée.

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Published: May 4, 2001

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Graul, R.C., Sadée, W. Evolutionary relationships among G protein-coupled receptors using a clustered database approach. AAPS PharmSci 3, 12 (2001). https://doi.org/10.1208/ps030212

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