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

Liang Jia; Shengju Li; Wenxuan Dai; Lingna Guo; Zhengrong Xu; Anne M Scott; Zhe Zhang; Jianfeng Ren; Qinghua Zhang; Thomas S Dexheimer; Yu-Wen Chung-Davidson; Richard R Neubig; Qian Li; Weiming Li

doi:10.1016/j.jbc.2021.101268

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

J Biol Chem. 2021 Nov;297(5):101268. doi: 10.1016/j.jbc.2021.101268. Epub 2021 Sep 30.

Authors

Liang Jia¹, Shengju Li², Wenxuan Dai², Lingna Guo², Zhengrong Xu³, Anne M Scott⁴, Zhe Zhang⁴, Jianfeng Ren⁵, Qinghua Zhang⁵, Thomas S Dexheimer⁶, Yu-Wen Chung-Davidson⁴, Richard R Neubig⁷, Qian Li⁸, Weiming Li⁹

Affiliations

¹ Center for Brain Science, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Fisheries and Wildlife, Michigan State University, East Lansing, Michigan, USA; College of Fisheries and Life Sciences, Shanghai Ocean University, Shanghai, China.
² Center for Brain Science, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Center for Brain Science, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
⁴ Department of Fisheries and Wildlife, Michigan State University, East Lansing, Michigan, USA.
⁵ College of Fisheries and Life Sciences, Shanghai Ocean University, Shanghai, China.
⁶ National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
⁷ Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA. Electronic address: rneubig@msu.edu.
⁸ Center for Brain Science, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, China. Electronic address: liqian@shsmu.edu.cn.
⁹ Department of Fisheries and Wildlife, Michigan State University, East Lansing, Michigan, USA. Electronic address: liweim@msu.edu.

Abstract

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 Asp^3.32 and Tyr^6.51 residues. sTAAR365, which has remarkable sensitivity for cadaverine (EC₅₀ = 4 nM), uses an extra residue, Thr^7.42, to stabilize ligand binding. These cadaverine recognition sites also interact with amines with four and three amino groups (spermine and spermidine, respectively). Glu^7.36 of sTAAR365 cooperates with Asp^3.32 and Thr^7.42 to recognize spermine, whereas mTAAR9 recognizes spermidine through an additional aromatic residue, Tyr^7.43. 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.

Keywords: G-protein coupled receptor (GPCR); biogenic amine; docking; homology modeling; ligand-recognition site; olfaction; polyamine; site-directed mutagenesis; structure–function; trace amine-associated receptor (TAAR).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Motifs
Animals
Binding Sites
Biogenic Polyamines / chemistry*
Fish Proteins / chemistry*
Fish Proteins / genetics
Fish Proteins / metabolism
HEK293 Cells
Humans
Lampreys
Mice
Molecular Docking Simulation*
Mutagenesis, Site-Directed
Receptors, Odorant / chemistry*
Receptors, Odorant / genetics
Receptors, Odorant / metabolism

Substances

Biogenic Polyamines
Fish Proteins
Receptors, Odorant