seven-transmembrane G protein-coupled receptor superfamily; This hierarchical evolutionary model represents the seven-transmembrane (7TM) receptors, often referred to as G protein-coupled receptors (GPCRs), which transmit physiological signals from the outside of the cell to the inside via G proteins. GPCRs constitute the largest known superfamily of transmembrane receptors across the three kingdoms of life that respond to a wide variety of extracellular stimuli including peptides, lipids, neurotransmitters, amino acids, hormones, and sensory stimuli such as light, smell and taste. All GPCRs share a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling is agonist-induced conformational changes in the receptors, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes. However, some 7TM receptors, such as the type 1 microbial rhodopsins, do not activate G proteins. Based on sequence similarity, GPCRs can be divided into six major classes: class A (the rhodopsin-like family), class B (the Methuselah-like, adhesion and secretin-like receptor family), class C (the metabotropic glutamate receptor family), class D (the fungal mating pheromone receptors), class E (the cAMP receptor family), and class F (the frizzled/smoothened receptor family). Nearly 800 human GPCR genes have been identified and are involved essentially in all major physiological processes. Approximately 40% of clinically marketed drugs mediate their effects through modulation of GPCR function for the treatment of a variety of human diseases including bacterial infections.

                         10        20        30
                 ....*....|....*....|....*....|.
gi 578828915 265 VHILTRISQAGCGVSMIFLAFTIILYAFLRC 295
Cdd:cd15442    1 AQTLVTISSAGCGVSMVFLIFTIILYFFLRF 31

orphan adhesion receptor GPR97, member of the class B2 family of seven-transmembrane G protein-coupled receptors; GPR97 is an orphan receptor that has been classified into the group VIII of adhesion GPCRs. Other members of the Group VII include GPR56, GPR64, GPR112, GPR114, and GPR126. GPR97 is identified as a lymphatic adhesion receptor that is specifically expressed in lymphatic endothelium, but not in blood vascular endothelium, and is shown to regulate migration of lymphatic endothelial cells via the small GTPases RhoA and cdc42. The adhesion receptors are characterized by the presence of large N-terminal extracellular domains containing multiple adhesion motifs, which play critical roles in cell-cell adhesion and cell-matrix interactions, that are coupled to a class B seven-transmembrane domain. Furthermore, almost all adhesion receptors, except GPR123, contain an evolutionarily conserved GPCR- autoproteolysis inducing (GAIN) domain that undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif located immediately N-terminal to the first transmembrane region, to generate N- and C-terminal fragments (NTF and CTF), which may serve important biological functions.

                         10        20        30
                 ....*....|....*....|....*....|.
gi 578828915 265 VHILTRISQAGCGVSMIFLAFTIILYAFLRC 295
Cdd:cd15442    1 AQTLVTISSAGCGVSMVFLIFTIILYFFLRF 31

orphan adhesion receptor GPR97, member of the class B2 family of seven-transmembrane G protein-coupled receptors; GPR97 is an orphan receptor that has been classified into the group VIII of adhesion GPCRs. Other members of the Group VII include GPR56, GPR64, GPR112, GPR114, and GPR126. GPR97 is identified as a lymphatic adhesion receptor that is specifically expressed in lymphatic endothelium, but not in blood vascular endothelium, and is shown to regulate migration of lymphatic endothelial cells via the small GTPases RhoA and cdc42. The adhesion receptors are characterized by the presence of large N-terminal extracellular domains containing multiple adhesion motifs, which play critical roles in cell-cell adhesion and cell-matrix interactions, that are coupled to a class B seven-transmembrane domain. Furthermore, almost all adhesion receptors, except GPR123, contain an evolutionarily conserved GPCR- autoproteolysis inducing (GAIN) domain that undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif located immediately N-terminal to the first transmembrane region, to generate N- and C-terminal fragments (NTF and CTF), which may serve important biological functions.

                         10        20        30
                 ....*....|....*....|....*....|.
gi 578828915 265 VHILTRISQAGCGVSMIFLAFTIILYAFLRC 295
Cdd:cd15442    1 AQTLVTISSAGCGVSMVFLIFTIILYFFLRF 31

orphan GPR126 and related proteins, group VIII adhesion GPCRs, member of the class B2 family of seven-transmembrane G protein-coupled receptors; Group VIII adhesion GPCRs include orphan GPCRs such as GPR56, GPR64, GPR97, GPR112, GPR114, and GPR126. GPR56 is involved in the regulation of oligodendrocyte development and myelination in the central nervous system via coupling to G(12/13) proteins, which leads to the activation of RhoA GTPase. GPR126, on the other hand, is required for Schwann cells, but not oligodendrocyte myelination in the peripheral nervous system. Gpr64 is mainly expressed in the epididymis of male reproductive tract, and targeted deletion of GPR64 causes sperm stasis and efferent duct blockage due to abnormal fluid reabsorption, resulting in male infertility. GPR64 is also over-expressed in Ewing's sarcoma (ES), as well as upregulated in other carcinomas from kidney, prostate or lung, and promotes invasiveness and metastasis in ES via the upregulation of placental growth factor (PGF) and matrix metalloproteinase (MMP) 1. GPR97 is identified as a lymphatic adhesion receptor that is specifically expressed in lymphatic endothelium, but not in blood vascular endothelium, and is shown to regulate migration of lymphatic endothelial cells via the small GTPases RhoA and cdc42. GPR112 is specifically expressed in normal enterochromatin cells and gastrointestinal neuroendocrine carcinoma cells, but its biological function is unknown. GPR114 is mainly found in granulocytes (polymorphonuclear leukocytes), and GPR114-transfected cells induced an increase in cAMP levels via coupling to G(s) protein. The adhesion receptors are characterized by the presence of large N-terminal extracellular domains containing multiple adhesion motifs, which play critical roles in cell-cell adhesion and cell-matrix interactions, that are coupled to a class B seven-transmembrane domain. Furthermore, almost all adhesion receptors, except GPR123, contain an evolutionarily conserved GPCR- autoproteolysis inducing (GAIN) domain that undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif located immediately N-terminal to the first transmembrane region, to generate N- and C-terminal fragments (NTF and CTF), which may serve important biological functions.

                         10        20        30
                 ....*....|....*....|....*....|
gi 578828915 265 VHILTRISQAGCGVSMIFLAFTIILYAFLR 294
Cdd:cd15258    1 LHILTFISYVGCGISAIFLAITILTYIAFR 30

class B family of seven-transmembrane G protein-coupled receptors; The class B of seven-transmembrane GPCRs is classified into three major subfamilies: subfamily B1 (secretin-like receptor family), B2 (adhesion family), and B3 (Methuselah-like family). The class B receptors have been identified in all the vertebrates, from fishes to mammals, as well as invertebrates including Caenorhabditis elegans and Drosophila melanogaster, but are not present in plants, fungi or prokaryotes. The B1 subfamily comprises receptors for polypeptide hormones of 27-141 amino-acid residues such as secretin, glucagon, glucagon-like peptide (GLP), calcitonin gene-related peptide, parathyroid hormone (PTH), and corticotropin-releasing factor. These receptors contain the large N-terminal extracellular domain (ECD), which plays a critical role in hormone recognition by binding to the C-terminal portion of the peptide. On the other hand, the N-terminal segment of the hormone induces receptor activation by interacting with the receptor transmembrane domains and connecting extracellular loops, triggering intracellular signaling pathways. All members of the subfamily B1 receptors preferentially couple to G proteins of G(s) family, which positively stimulate adenylate cyclase, leading to increased intracellular cAMP formation and calcium influx. The subfamily B2 consists of cell-adhesion receptors with 33 members in humans and vertebrates. The adhesion receptors are characterized by the presence of large N-terminal extracellular domains containing a variety of structural motifs, which play critical roles in cell-cell adhesion and cell-matrix interactions, linked to a class B seven-transmembrane domain. These include, for example, EGF (epidermal growth factor)-like domains in CD97, Celsr1 (cadherin family member), Celsr2, Celsr3, EMR1 (EGF-module-containing mucin-like hormone receptor-like 1), EMR2, EMR3, and Flamingo; two laminin A G-type repeats and nine cadherin domains in Flamingo and its human orthologs Celsr1, Celsr2 and Celsr3; olfactomedin-like domains in the latrotoxin receptors; and five or four thrombospondin type 1 repeats in BAI1 (brain-specific angiogenesis inhibitor 1), BAI2 and BAI3. Almost all adhesion receptors, except GPR123, contain an evolutionarily conserved GPCR- autoproteolysis inducing (GAIN) domain that undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif located immediately N-terminal to the first transmembrane region, to generate N- and C-terminal fragments (NTF and CTF), which may serve important biological functions. Furthermore, the subfamily B3 includes Methuselah (Mth) protein, which was originally identified in Drosophila as a GPCR affecting stress resistance and aging, and its closely related proteins.

                         10        20
                 ....*....|....*....|....*...
gi 578828915 267 ILTRISQAGCGVSMIFLAFTIILYAFLR 294
Cdd:cd13952    3 ALSIITYIGCSLSLVGLLLTIITYLLFP 30