Elimination of a ligand gating site generates a supersensitive olfactory receptor.
Olfaction poses one of the most complex ligand-receptor matching problems in biology due to the unparalleled multitude of odor molecules facing a large number of cognate olfactory receptors. We have recently deorphanized an olfactory receptor, TAAR13c, as a specific receptor for the death-associated odor cadaverine. Here we have modeled the cadaverine/TAAR13c interaction, exchanged predicted binding residues by site-directed mutagenesis, and measured the activity of the mutant receptors. Unexpectedly we observed a binding site for cadaverine at the external surface of the receptor, in addition to an internal binding site, whose mutation resulted in complete loss of activity. In stark contrast, elimination of the external binding site generated supersensitive receptors. Modeling suggests this site to act as a gate, limiting access of the ligand to the internal binding site and thereby downregulating the affinity of the native receptor. This constitutes a novel mechanism to fine-tune physiological sensitivity to socially relevant odors.
Institute of Genetics, Biocenter, University at Cologne, Zülpicherstrasse 47a, 50674 Cologne, Germany.
Kanika
K
Sharma
Institute of Genetics, Biocenter, University at Cologne, Zülpicherstrasse 47a, 50674 Cologne, Germany.
Gaurav
G
Ahuja
Institute of Genetics, Biocenter, University at Cologne, Zülpicherstrasse 47a, 50674 Cologne, Germany.
Ashiq
A
Hussain
Institute of Complex Systems (ICS-4), Research Center Jülich, 52428 Jülich, Germany.
Sabine
S
Balfanz
Institute of Complex Systems (ICS-4), Research Center Jülich, 52428 Jülich, Germany.
Arnd
A
Baumann
Institute of Genetics, Biocenter, University at Cologne, Zülpicherstrasse 47a, 50674 Cologne, Germany.
Sigrun I
SI
Korsching
D000818:Animals; D001665:Binding Sites; D002103:Cadaverine / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009812:Odorants; D018034:Olfactory Receptor Neurons / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D018035:Receptors, Odorant / Q000737:chemistry / Q000235:genetics*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics*
D008024:Ligands; D018035:Receptors, Odorant; D029961:Zebrafish Proteins; C000627750:taar13c protein, zebrafish; D002103:Cadaverine