Convergent olfactory trace amine-associated receptors detect biogenic polyamines with distinct motifs via a conserved binding site

• Published in: The Journal of biological chemistry Vol. 297; no. 5; p. 101268
• Main Authors: Jia, Liang, Li, Shengju, Dai, Wenxuan, Guo, Lingna, Xu, Zhengrong, Scott, Anne M., Zhang, Zhe, Ren, Jianfeng, Zhang, Qinghua, Dexheimer, Thomas S., Chung-Davidson, Yu-Wen, Neubig, Richard R., Li, Qian, Li, Weiming
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2021; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Motifs; Animals; Binding Sites; biogenic amine; Biogenic Polyamines - chemistry; docking; Fish Proteins - chemistry; Fish Proteins - genetics; Fish Proteins - metabolism; G-protein coupled receptor (GPCR); HEK293 Cells; homology modeling; Humans; Lampreys; ligand-recognition site; Mice; Molecular Docking Simulation; Mutagenesis, Site-Directed; olfaction; polyamine; Receptors, Odorant - chemistry; Receptors, Odorant - genetics; Receptors, Odorant - metabolism; site-directed mutagenesis; structure–function; trace amine-associated receptor (TAAR); SPD; Gαolf; olfaction; polyamine; DMEM; SPM; homology modeling; sTAAR365; ligand-recognition site; EC50; G-protein coupled receptor (GPCR); Emax; site-directed mutagenesis; CAD; biogenic amine; PUT; mTAAR9; docking; TEA; mRTPs; GPCR; TAAR; trace amine-associated receptor (TAAR); TR-FRET assay; structure–function
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2021.101268

Biogenic amines activate G-protein-coupled receptors (GPCRs) in the central nervous system in vertebrate animals. Several biogenic amines, when excreted, stimulate trace amine-associated receptors (TAARs), a group of GPCRs in the main olfactory epithelium, and elicit innate behaviors. How TAARs recognize amines with varying numbers of amino groups is largely unknown. We reasoned that a comparison between lamprey and mammalian olfactory TAARs, which are thought to have evolved independently but show convergent responses to polyamines, may reveal structural determinants of amine recognition. Here, we demonstrate that sea lamprey TAAR365 (sTAAR365) responds strongly to biogenic polyamines cadaverine, putrescine, and spermine, and shares a similar response profile as a mammalian TAAR (mTAAR9). Docking and site-directed mutagenesis analyses show that both sTAAR365 and mTAAR9 recognize the two amino groups of cadaverine with the conserved Asp3.32 and Tyr6.51 residues. sTAAR365, which has remarkable sensitivity for cadaverine (EC50 = 4 nM), uses an extra residue, Thr7.42, to stabilize ligand binding. These cadaverine recognition sites also interact with amines with four and three amino groups (spermine and spermidine, respectively). Glu7.36 of sTAAR365 cooperates with Asp3.32 and Thr7.42 to recognize spermine, whereas mTAAR9 recognizes spermidine through an additional aromatic residue, Tyr7.43. These results suggest a conserved mechanism whereby independently evolved TAAR receptors recognize amines with two, three, or four amino groups using the same recognition sites, at which sTAAR365 and mTAAR9 evolved distinct motifs. These motifs interact directly with the amino groups of the polyamines, a class of potent and ecologically important odorants, mediating olfactory signaling.