Sequence similarities between a novel putative G protein-coupled receptor and Na+/Ca2+ exchangers define a cation binding domain

cDNA clones encoding a novel putative G protein-coupled receptor have been characterized. The receptor is widely expressed in normal solid tissues. Co nsisting of 1967 amino acid residues, this receptor is one of the largest k nown and is therefore referred to as a very large G protein-coupled recepto r, or VLGR1. It is most closely related to the secretin family of G protein -coupled receptors based on similarity of the sequences of its transmembran e segments. As demonstrated by cell surface labeling with a biotin derivati ve, the recombinant protein is expressed on the surface of transfected mamm alian cells. Whereas several other recently described receptors in this fam ily also have large extracellular domains, the large extracellular domain o f VLGR1 has a unique structure. It has nine imperfectly repeated units that are rich in acidic residues and are spaced at intervals of approximately 1 20 amino acid residues. These repeats resemble the regulatory domains of Na +/Ca2+ exchangers as well as a component of an extracellular aggregation fa ctor of marine sponges. Bacterial fusion proteins containing two or four re peats specifically bind Ca-45 in overlay experiments; binding is competed p oorly by Mg2+ but competed well by neomycin, Al3+, and Gd3+. These results define a consensus cation binding motif employed in several widely divergen t types of proteins. The ligand for VLGR1, its function, and the signaling pathway(s) it employs remain to be defined.