GRAFS Classification of 7TMRs

The five main families identified from multiple sequence alignment, with high bootstrap support, are designated glutamate, rhodopsin, adhesion, frizzled/taste2, and secretin. The first letters of the five family names constitute the GRAFS acronym designation. The rhodopsin and glutamate designations conform to the original A and C families, whereas family B has been split into the secretin GPCR family and the related but distinct non-GPCR adhesion family, with 7TMR sequences characterized by long amino terminal repeats, from 200 to 2800 residues, and with no signal transduction modalities as yet identified. Some of the recently identified taste receptors join either the glutamate group or the frizzled group, and all these peripheral members (except for the recent prokaryotic survey3 examples) are now incorporated into the superfamily.

Chromosomal assignments of the phylogenetic groups conform to the known paralogy groups of the human genome, reinforcing the concepts of an ancient tetraploidic event and of duplication for chromosomes 4 and 5. The various para-logons are characterized by clusters of gene duplication and diversification, especially the more recently expanded chemokine cluster. Evidence of domain shuffling is observed for the more ancient adhesion receptors, with their large and repetitive extracellular domains consistent with the advent of metazoan complexity. (Within the discursive text,8 certain receptor names have migrated confusingly into the wrong subfamily, including the receptors for TRH, cysteinyl-leukotrienes, and the immune formyl peptide.)

The rhodopsin segment of the GRAFS classification now includes the 460 or so olfactory receptors in the classical family A. Fredriksson and coauthors8 identified four rhodopsin subfamilies designated a, p, g, and d (Figure 10.2). The a subfamily of rhodopsin receptors includes a prostaglandin, a monoamine, an opsin, and a melatonin receptor cluster. A fifth more diverse cluster incorporates the adenosine and cannabinoid receptors as well as the Edg receptors for charged lipids and the melanocortin receptors that bind a tridecapeptide. The p subfamily includes the major peptide hormones of the hypothalamus, pituitary, and digestive tract. The g

Grafs Classification

FIGURE 10.2 Concurrence of phylogenetic and functional classifications of 7TMRs. The GRAFS phylogenetic unrooted tree of rhodopsin receptors defines the abgd subfamily branches by a high bootstrap value.8 The asterisk denotes the branching point for the 460 olfactory receptors. Areas incorporating numerous related receptor branches are identified by representative ligands and shaded according to the four ligand classes defined in Figure 10.1: ® monoamines, © amphipathic ligands, ® flexible peptides, and ® complex globular proteins, in order of increasing molecular weight. The four ligand classes/receptor subfamilies can be designated a — aminergic, b — brain-gut peptide, g — Gi protein ligand, and 5 — diverse ligand class or receptor subfamily.

FIGURE 10.2 Concurrence of phylogenetic and functional classifications of 7TMRs. The GRAFS phylogenetic unrooted tree of rhodopsin receptors defines the abgd subfamily branches by a high bootstrap value.8 The asterisk denotes the branching point for the 460 olfactory receptors. Areas incorporating numerous related receptor branches are identified by representative ligands and shaded according to the four ligand classes defined in Figure 10.1: ® monoamines, © amphipathic ligands, ® flexible peptides, and ® complex globular proteins, in order of increasing molecular weight. The four ligand classes/receptor subfamilies can be designated a — aminergic, b — brain-gut peptide, g — Gi protein ligand, and 5 — diverse ligand class or receptor subfamily.

subfamily has three major branches: one for the galanin, somatostatin, and opioid receptors; another incorporating immune ligands such as the chemokines, formyl peptide, and leukotrienes with, unexpectedly, angiotensin/bradykinin; and a third branch populated by the two representatives of the 19-mer melanin-concentrating hormone. The 5 subfamily includes an estimated 460 olfactory receptors, a few MAS1 oncogene-like receptors, the glycoprotein hormone receptor cluster, and a large purine receptor cluster that surprisingly brings receptors for the thrombins and cysteinyl-leukotrienes together.

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