Conserved C-terminal motifs in odorant receptors instruct their cell surface expression and cAMP signaling

Odorant receptors are sensor proteins for food aromas and other volatile stimuli in our environment. These receptors are integral membrane proteins, which are typically expressed in the cilia of olfactory sensory neurons of our nose. Research on odorant receptors is typically done in test cell systems, which requires their expression at the cell surface. ‘Zip codes’ of intracellular amino acid motifs of membrane proteins typically guide both, their interaction with other proteins, and their intracellular transport. Such motifs have been unknown for the odorant receptors, so far. Here we identified highly conserved C-terminal amino acid motifs, which discriminate between class-II and the majority of phylogenetic older class-I odorant receptors, by investigating 4808 receptors across eight species. These motifs had a differential impact on cell surface expression and odorant-induced cAMP signaling of individual recombinant receptors in a test cell system. We demonstrate combinations of distinct C-terminal motifs to be necessary and instructive for the cell surface targeting and intracellular signaling of odorant receptors. We may speculate that an individual ‘zip-coding’ of odorant receptors with C-terminal motifs, that control their surface expression and intracellular signaling, may be instructive for a specific wiring of olfactory sensory neurons to class-I or class-II odorant receptor-related brain areas. This may be an important mechanism of odorant coding from the nose to the brain. The data set includes all 4008 C-terminal sequences with accession numbers, sorted by class, in an Excel file. Motif statistics are calculated for each species