title: Non-classical amine recognition evolved in a large clade of olfactory receptors.
abstract: Biogenic amines are important signaling molecules, and the structural basis for their recognition by G Protein-Coupled Receptors (GPCRs) is well understood. Amines are also potent odors, with some activating olfactory trace amine-associated receptors (TAARs). Here, we report that teleost TAARs evolved a new way to recognize amines in a non-classical orientation. Chemical screens de-orphaned eleven zebrafish TAARs, with agonists including serotonin, histamine, tryptamine, 2-phenylethylamine, putrescine, and agmatine. Receptors from different clades contact ligands through aspartates on transmembrane α-helices III (canonical Asp(3.32)) or V (non-canonical Asp(5.42)), and diamine receptors contain both aspartates. Non-classical monoamine recognition evolved in two steps: an ancestral TAAR acquired Asp(5.42), gaining diamine sensitivity, and subsequently lost Asp(3.32). Through this transformation, the fish olfactory system dramatically expanded its capacity to detect amines, ecologically significant aquatic odors. The evolution of a second, alternative solution for amine detection by olfactory receptors highlights the tremendous structural versatility intrinsic to GPCRs.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Yaw
authors.initials: Y
authors.lastname: Tachie-Baffour
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Zhikai
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Organismic and Evolutionary Biology, Museum of Comparative Zoology, Harvard University, Cambridge, United States.
authors.forename: Maude W
authors.initials: MW
authors.lastname: Baldwin
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Kruse
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Liberles
mesh_terms: D000588:Amines / Q000378:metabolism*; D000818:Animals; D019143:Evolution, Molecular; D008958:Models, Molecular; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics; D015027:Zebrafish / Q000235:genetics / Q000502:physiology*
chemical_list: D000588:Amines; D043562:Receptors, G-Protein-Coupled
keywords: G Protein-Coupled Receptor; biochemistry; evolutionary biology; genomics; ligand recognition; molecular evolution; odorant receptors; olfaction; zebrafish