title: Activation of pheromone-sensitive neurons is mediated by conformational activation of pheromone-binding protein.
abstract: Detection of volatile odorants by olfactory neurons is thought to result from direct activation of seven-transmembrane odorant receptors by odor molecules. Here, we show that detection of the Drosophila pheromone, 11-cis vaccenyl acetate (cVA), is instead mediated by pheromone-induced conformational shifts in the extracellular pheromone-binding protein, LUSH. We show that LUSH undergoes a pheromone-specific conformational change that triggers the firing of pheromone-sensitive neurons. Amino acid substitutions in LUSH that are predicted to reduce or enhance the conformational shift alter sensitivity to cVA as predicted in vivo. One substitution, LUSH(D118A), produces a dominant-active LUSH protein that stimulates T1 neurons through the neuronal receptor components Or67d and SNMP in the complete absence of pheromone. Structural analysis of LUSH(D118A) reveals that it closely resembles cVA-bound LUSH. Therefore, the pheromone-binding protein is an inactive, extracellular ligand converted by pheromone molecules into an activator of pheromone-sensitive neurons and reveals a distinct paradigm for detection of odorants.
authors.affiliation: Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, 12801 East 17th Avenue, M/S 8303, P.O. Box 6511, Aurora CO 80045.
authors.forename: John D
authors.initials: JD
authors.lastname: Laughlin
authors.affiliation: Department of Pharmacology and Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd. Dallas, TX 75390-9111.
authors.forename: Tal Soo
authors.initials: TS
authors.lastname: Ha
authors.affiliation: Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, 12801 East 17th Avenue, M/S 8303, P.O. Box 6511, Aurora CO 80045.|Program in Biomolecular Structure, University of Colorado at Denver and Health Sciences Center, 12801 East 17th Avenue, M/S 8303, P.O. Box 6511, Aurora CO 80045.
authors.forename: David N M
authors.initials: DNM
authors.lastname: Jones
authors.affiliation: Department of Pharmacology and Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd. Dallas, TX 75390-9111.
authors.forename: Dean P
authors.initials: DP
authors.lastname: Smith
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism*; D005260:Female; D008297:Male; D008958:Models, Molecular; D009829:Oleic Acids / Q000737:chemistry / Q000378:metabolism; D018034:Olfactory Receptor Neurons / Q000737:chemistry / Q000378:metabolism*; D010675:Pheromones / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000378:metabolism; D018035:Receptors, Odorant / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D043563:Receptors, Pheromone / Q000378:metabolism; D012724:Sex Attractants / Q000378:metabolism*
chemical_list: D000085:Acetates; D029721:Drosophila Proteins; D009829:Oleic Acids; C530080:Or67d protein, Drosophila; D010675:Pheromones; D011956:Receptors, Cell Surface; D018035:Receptors, Odorant; D043563:Receptors, Pheromone; D012724:Sex Attractants; C524729:Snmp1 protein, Drosophila; C505385:cis-vaccenyl acetate; C045648:odorant-binding protein