Odorant Receptor Paralogy and Selectivity

Example 3

Amino acids sequences alignment shows 67% identity between OR5A1 and OR5A2, 58% with OR5AN1 and 41% with OR11A1 (FIGS. 2A-B). To further address the question of how well paralogy predicts functionality and selectivity, we compared the response of these ORs to beta-ionone and 2-ethyl fenchol, the two well-known agonists of OR5A1 and OR11A1 respectively (Jaeger et al., 2013; Adipietro et al., 2012). These compounds were tested in concentration-response analysis in luciferase assays, as described previously. In each experiment, an empty vector was used as negative control (pEFIBRHO). Representative concentration-response curves are given in FIGS. 3A-B.

It was observed that OR5A1, the closest paralog of OR5A2, and OR11A1 are both activated by their own cognate agonist. On the contrary, in these experimental conditions, OR of the invention (namely OR5A2) as well as OR5AN1 are stimulated neither by beta-ionone nor by 2 ethyl-fenchol, both showing concentration-response curves similar to the empty vector.

Altogether, these results indicate that OR5A1 and OR5A2, although members of the same subfamily, show different agonist specificity (beta-ionone vs musk) indicating that amino acids similarity doesn't robustly predict OR selectivity and functionality among paralogs.