Epididymal G protein-coupled receptor (GPCR): two hats and a two-piece suit tailored at the GPS motif.
G protein-coupled receptors (GPCRs) are involved in cell recognition and signaling and their function has been experimentally determined by ligand activation and site-directed mutagenesis. Structurally, GPCRs consist of an extracellular N-terminus and an intracellular C-terminus separated by seven helical transmembrane domains (TM7). The extracellular region is highly glycosylated. The intracellular region binds to G proteins. An epididymal GPCR, designated HE6 (for human epididymis-specific protein 6), is present in the stereocilia projecting from the apical domain of principal cells into the epididymal lumen. In conceptual terms, HE6 wears two hats: an unusually long extracellular region characteristic of cell adhesion proteins, and an intracellular region with binding affinity to G protein. The binding partner to the long extracellular region has not been identified. HE6 has another remarkable feature comparable to the GPCR calcium-independent receptor of alpha-latrotoxin, designated CIRL. Both HE6 and CIRL are endogenously cleaved into two pieces at the GPCR proteolytic site (GPS) located adjacent to TM1, the first of the seven transmembrane helices. One fragment of the heterodimer wears the cell adhesion hat; the other retains the typical characteristics of GPCRs. This proteolytic processing may be regarded as a mechanism of molecular compartmentalization of cell adhesion and G protein activation functions. The latter may engage a beta-arrestin-driven endocytic trafficking mechanism independent from the adhesive properties of the mucin extracellular domain. It is also conceivable that events taking place in the epididymal lumen can be surveyed by the long adhesive rod and subsequently coupled inside principal cells to a signaling cascade.
Kierszenbaum
Abraham L
AL
Department of Cell Biology and Anatomical Sciences, The City University of New York Medical School, New York, New York 10031, USA. kier@med.cuny.edu
D004822:Epididymis / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008958:Models, Molecular; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled
C105986:ADGRG2 protein, human; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D019204:GTP-Binding Proteins