Adhesion G protein-coupled receptor
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.
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.
[4] 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.
They are believed to have evolved from the cAMP receptor family, arising approximately 1275 million years ago before the split of Unikonts from a common ancestor.
[11] Genome analysis of the Teleost Takifugu rubripes has revealed that it has only two adhesion GPCRs that showed homology to Ig-hepta/GPR116.
The binding of collagen III to GPR56 occurs on the N-terminus and has been narrowed down to a short stretch of amino acids.
Research groups are working to elucidate the downstream signaling molecules utilizing several methods, including chemical screens and analysis of second messenger levels in over-expressed cells.
[15] It has been shown that overexpressing GPCRs in vitro can result in receptor activation in the absence of a ligand or agonist.
Many adhesion GPCRs undergo proteolytic events posttranslationally at highly conserved Cys-rich motifs known as GPCR proteolysis sites (GPS), located next to the first transmembrane region.
In the aptly named Very Large G protein-coupled Receptor 1 VLGR1 the extracellular region extends up to almost 6000 amino acids.
[19] Since 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 particular, members the EGF-TM7 subfamily which possess N-terminal EGF-like domains are predominantly restricted to leukocytes suggesting a putative role in immune function.
The adhesion‑GPCR brain angiogenesis inhibitor 1 (BAI1) acts as a phosphatidylserine receptor playing a potential role in the binding and clearance of apoptotic cells, and the phagocytosis of Gram-negative bacteria.
Knockouts of this adhesion GPCR in both Danio rerio and Mus musculus result in an arrest at the promyelinating stage.
Many mutations affect function via decreased cell surface expression or inhibition of autoproteolysis within the GAIN domain.
Mutations in GPR56 result in bilateral frontoparietal polymicrogyria in humans, characterized by abnormal neuronal migration and surface ectopias.,[33] Variants of GPR126 have been associated with adolescent idiopathic scoliosis,[34] as well as being responsible for severe arthrogryposis multiplex congenita.
