A Ligand, Not a Carrier

Abstract

Volatile odorants are generally thought to bind to G protein-coupled receptors and thereby activate a downstream signaling pathway, a paradigm challenged by data from Laughlin et al . In Drosophila , various odorant-binding proteins are secreted into the lymph around subsets of olfactory neurons (where odorants diffuse); the function of these pheromone- and odorant-binding proteins, however, has been unclear (see Stowers and Logan). Laughlin et al ., from a research group that previously showed that the odorant-binding protein LUSH is required for sensitivity to the pheromone 11- cis vaccenyl acetate (cVA), combined structural and in vivo electrophysiological analysis to investigate its function. Comparison of the x-ray crystal structure of LUSH bound to cVA with the previously determined structure of uncomplexed LUSH revealed that binding by cVA (which was almost completely enclosed by LUSH) induced a conformational change in LUSH. A LUSH mutant bearing an amino acid substitution predicted to minimize this conformational change was less effective at conferring cVA sensitivity to T1 neurons (which mediate the response to this pheromone) in flies lacking endogenous LUSH than was wild-type LUSH. In contrast, a mutation predicted to enhance the conformational change produced a more effective form. Moreover, a mutation yielding an uncomplexed LUSH conformation that resembled that of the cVA-bound form stimulated T1 neurons even in the absence of cVA, an ability that depended on the expression in T1 neurons of Or67d and SNMP (which are required for sensitivity to cVA). Thus, the authors conclude that LUSH is an inactive ligand that is converted into an active form through cVA binding. J. D. Laughlin, T. S. Ha, D. N. M. Jones, D. P. Smith, Activation of pheromone-sensitive neurons is mediated by conformational activation of pheromone-binding protein. Cell 133 , 1255-1265 (2008). [PubMed] L. Stowers, D. W. Logan, LUSH shapes up for a starring role in olfaction. Cell 133 , 1137-1139 (2008). [PubMed]