title: The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints.
abstract: The superfamily of G-protein-coupled receptors (GPCRs) is very diverse in structure and function and its members are among the most pursued targets for drug development. We identified more than 800 human GPCR sequences and simultaneously analyzed 342 unique functional nonolfactory human GPCR sequences with phylogenetic analyses. Our results show, with high bootstrap support, five main families, named glutamate, rhodopsin, adhesion, frizzled/taste2, and secretin, forming the GRAFS classification system. The rhodopsin family is the largest and forms four main groups with 13 sub-branches. Positions of the GPCRs in chromosomal paralogons regions indicate the importance of tetraploidizations or local gene duplication events for their creation. We also searched for "fingerprint" motifs using Hidden Markov Models delineating the putative inter-relationship of the GRAFS families. We show several common structural features indicating that the human GPCRs in the GRAFS families share a common ancestor. This study represents the first overall map of the GPCRs in a single mammalian genome. Our novel approach of analyzing such large and diverse sequence sets may be useful for studies on GPCRs in other genomes and divergent protein families.
authors.affiliation: Department of Neuroscience, Biomedical Center, Box 593, 75 124 Uppsala, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Fredriksson
authors.forename: Malin C
authors.initials: MC
authors.lastname: Lagerström
authors.forename: Lars-Gustav
authors.initials: LG
authors.lastname: Lundin
authors.forename: Helgi B
authors.initials: HB
authors.lastname: Schiöth
mesh_terms: D002874:Chromosome Mapping; D019204:GTP-Binding Proteins / Q000145:classification* / Q000235:genetics; D015894:Genome, Human; D006801:Humans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000145:classification* / Q000235:genetics; D010802:Phylogeny; D019038:Platelet Glycoprotein GPIb-IX Complex; D011956:Receptors, Cell Surface / Q000145:classification* / Q000235:genetics; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone / Q000145:classification / Q000235:genetics; D017470:Receptors, Glutamate / Q000145:classification / Q000235:genetics; D012243:Rhodopsin / Q000145:classification / Q000235:genetics; D020539:Sequence Analysis, Protein; D017386:Sequence Homology, Amino Acid
chemical_list: D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; D017470:Receptors, Glutamate; C094990:adhesion receptor; C029937:secretin receptor; D012243:Rhodopsin; D019204:GTP-Binding Proteins