Adhesion-GPCRs

GPCRs represent the largest superfamily of receptors in the human genome. Present on every cell and responding to a plethora of stimuli, GPCRs are involved in a great variety of physiological processes. According to the GRAFS classification system, GPCRs can be divided into five classes named Glutamate, Rhodopsin, Adhesion, Frizzled/taste, and Secretin. By far the largest and best understood is the Rhodopsin class that includes all classical GPCRs as well as hundreds of olfactory receptors. However, the second largest class is that of the adhesion-GPCRs.

The adhesion class comprises 33 members in humans with a broad distribution in embryonic and larval cells, cells of the reproductive tract, neurons, leukocytes, and a variety of tumours. Adhesion-GPCRs are found throughout metazeons and are also found in single-celled colony forming choanoflagellates such as Monosiga brevicollis and unicellular organisms such as Filasterea. The defining feature of adhesion-GPCRs that sets it apart from other GPCRs are their hybrid molecular structure. The extracellular region of adhesion-GPCRs can be exceptionally long and contain a variety of structural domains that are known for the ability to facilitate cell and matrix interactions. Their extracellular region contains the membrane proximal GAIN (GPCR-Autoproteolsis INducing) domain. Crystallographic and experimental data has shown this structurally conserved domain to mediate autocatalytic processing at a GPCR-proteolytic site (GPS) proximal to the first transmembrane helix. Autocatalytic processing gives rise to an extracellular (α) and a membrane-spanning (β) subunit, which are associated non-covalently, resulting in expression of a heterodimeric receptor at the cell surface. Ligand profiles and in vitro studies have indicated a role for adhesion-GPCRs in cell adhesion and migration. More recent work utilizing genetic models confined this concept by demonstrating that the primary function of adhesion-GPCRs may relate to the proper positioning of cells in a variety of organ systems. Moreover, growing evidence implies a role of adhesion-GPCRs in tumour cell metastasis. Recently, formal G protein-coupled signalling has been demonstrated for a number for adhesion-GPCRs, however, the orphan receptor status of many of the receptors still hampers full characterisation of potential signal transduction pathways. In 2011, a consortium of international scientists was established to facilate research into of the physiological and pathological functions of adhesion-GPCRs adhesion-GPCR consortium.



Human adhesion-GPCRs
BAI1, BAI2, BAI3, GPR56, GPR64, GPR97, VLGR1, GPR112, GPR114, GPR126, GPR128, EMR1, EMR2, EMR3, EMR4, CD97, LPHN1, LPHN2; LPHN3, ETLD1, GPR123, GPR124, GPR125, CELSR1, CELSR2, CELSR3, GPR133, GPR144, GPR110, GPR111, GPR113, GPR115, GPR116

Classification
The GPCR superfamily is the largest gene family in the human genome containing approximately 800 genes. As the vertebrate superfamily can be phylogenetic grouped into five main families theh GRAFS classification sytem has been proposed Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, Secretin) has been proposed.

Cleavage
One posttranslational modification that occurs in the majority of adhesion-GPCRs is a proteolytic cleavage event. Proteolysis occurs at a highly conserved Cys-rich motif known as the GPCR proteolysis site (GPS) proximal to the first transmembrane region. The cleavage occurs at a HL-S(T) site which is conserved from mammals to unicellular eukaryotes. Interestingly, once cleaved both subunits are expressed at the cell surface as a non-covalently associated heterodimer. As almost all adhesion-GPCRs possess the consensus GPS sequence, it is thought the majority of adhesion-GPCRs are expressed on the membrane as a two-subunit complex. Studies have shown that unlike most protein cleavage events, which are mediated via separate proteases, cleavage of adhesion-GPCRs cleavage is mediated via a domain within the protein itself. The intramolecular autocatalytic proteolysis is mediated by the structurally conserved GAIN domain. This domain is prodominantly found in adhesion-GPCRs but is also found in other multi-spanning transmembrane proteins, such as the sea urchin sperm receptor for egg jelly-1 (suREJ1), suREJ3 and polycystin-1. Structural analysis of two different GAIN domains, show that despite low sequence homology the domains of ~300 amino acids show high structural homology. The mechanism of cleavage is believed to be similar to other auto-proteolytic molecules such as Ntn hydrolases and hedgehog proteins. NON GPS cleavage required

Domains
One characteristic of adhesion-GPCRs is their extended extracellular region. This region is modular in nature, often posessing a variety of struturally-defined protein domains in addition to the membrane proximal GAIN domain. In the aptly named Very Large G protein-coupled Receptor 1 VLGR1 the extracellular region extends up to almost 6000 amino acids. Human adhesion-GPCRs possess domains including EGF-like, Cadherin , thrombospondin , Immunoglobulin , Pentraxin , Calx-beta and Leucine-rich repeats. In non-vertebrate species multiple other strucurally motifs including Kringle, Somatomedin B, SRCR may be contained with the extracellular region. As many of these domains have been demonstrated to mediate protein-protein interactions within other proteins, they are believed to play the same role in adhesion-GPCRs. In deed, many ligands have been discovered for adhesion-GPCRs (see ligands section). Many of the adhesion-GPCR possess long stretches of amino acids with little homology to known protein domains suggesting the possibility of new structural domains being elucidated within their extracellular regions.

Immune system
A number of adhesion-GPCRs may have important roles within the immune system. In particular, members the EGF-TM7 subfamily which possess N-terminal EGF-like domains are prodominantly restricted to leukocytes suggesting a putative role in immune function. The human EGF‑TM7 family is composed of CD97, EMR1 (F4/80 receptor orthologue)  EMR2, EMR3 and EMR4 (a probable pseudogene in humans). The human-restricted EMR2 receptor, is expressed by myeloid cells including monocytes, dendritic cells and neutrophils has been shown to be involved in the activation and migration of human neutrophils and upregulated in patients suffering from systemic inflammatory response syndrome (SIRS). Details of EMR1, CD97 needed. The adhesion‑GPCR brain angiogenesis inhibitor 1 (BAI1) was initially presumed to be CNS specific but has since been shown to act as a phosphatidylserine receptor playing a potential role in the binding and clearance of apoptotic cells, and the phagocytosis of Gram-negative bacteria. GPR56 has recently been shown to a marker for inflammatory NK cell subsets and to be expressed by cytotoxic lymphocytes.