Proteins with multiple G protein-coupled receptor domains

Abstract

Currently known G protein-coupled receptors (GPCRs) have a single transmembrane domain. Many GPCRs form dimers that have two transmembrane domains (one per protein), and there are indications that this dimeric interaction is functionally meaningful. Here, based on sequence analysis and structure predictions, we report the existence of 57 proteins with two, three, or four GPCR domains within the same protein chain. We analyze the structures of these multi-GPCRs and show that almost all have DRY/NPxxY motifs, a strong indication of signaling activity. By homology, most of the multi-GPCRs that we identified are olfactory-related; a few are chemokine-related. Multi-GPCR candidates are found in various Chordata species including fish, camel, marmite, Chinese hamster, and new world monkeys. The discovery of receptors with multiple transmembrane domains suggests the possibility for signal regulation and amplification within an individual receptor, revealing another step in GPCR evolution and a new layer of complexity in signal transduction.

From a binding module to essential catalytic activity: how nature stumbled on a good thing

“…Duplication of the DfrB gene for translation in tandem as a single polypeptide could theoretically overcome this limitation. Indeed, the strategy of duplication in homomeric complexes is observed in other proteins, 88,89 and laboratory creation of tandem DfrB involving up to four fused repeats yielded a functional enzyme with similar efficiency. 90,91 The tandem DfrB constructs allowed examination of asymmetric substitutions; despite informing on the importance of specific interactions between residues and substrates, none yielded a more efficient enzyme.…”