Non-classical amine recognition evolved in a large clade of olfactory receptors

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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.

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Qian Li

Department of Cell Biology, Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Yaw Tachie-Baffour

Department of Cell Biology, Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Zhikai Liu

Department of Cell Biology, Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Maude W Baldwin

Department of Organismic and Evolutionary Biology, Museum of Comparative Zoology, Harvard University, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Andrew C Kruse

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Stephen D Liberles

Department of Cell Biology, Harvard Medical School, Boston, United States

For correspondence
Stephen_liberles@hms.harvard.edu

Competing interests
The authors declare that no competing interests exist.

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