title: Heterodimerization with Its splice variant blocks the ghrelin receptor 1a in a non-signaling conformation: a study with a purified heterodimer assembled into lipid discs.
abstract: Heterodimerization of G protein-coupled receptors has an impact on their signaling properties, but the molecular mechanisms underlying heteromer-directed selectivity remain elusive. Using purified monomers and dimers reconstituted into lipid discs, we explored how dimerization impacts the functional and structural behavior of the ghrelin receptor. In particular, we investigated how a naturally occurring truncated splice variant of the ghrelin receptor exerts a dominant negative effect on ghrelin signaling upon dimerization with the full-length receptor. We provide direct evidence that this dominant negative effect is due to the ability of the non-signaling truncated receptor to restrict the conformational landscape of the full-length protein. Indeed, associating both proteins within the same disc blocks all agonist- and signaling protein-induced changes in ghrelin receptor conformation, thus preventing it from activating its cognate G protein and triggering arrestin 2 recruitment. This is an unambiguous demonstration that allosteric conformational events within dimeric assemblies can be directly responsible for modulation of signaling mediated by G protein-coupled receptors.
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), CNRS UMR 5247, Université Montpellier 1, Faculté de Pharmacie, 15 avenue Charles Flahault, BP 14491, 34093 Montpellier Cedex 5, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Mary
authors.forename: Jean-Alain
authors.initials: JA
authors.lastname: Fehrentz
authors.forename: Marjorie
authors.initials: M
authors.lastname: Damian
authors.forename: Gérald
authors.initials: G
authors.lastname: Gaibelet
authors.forename: Hélène
authors.initials: H
authors.lastname: Orcel
authors.forename: Pascal
authors.initials: P
authors.lastname: Verdié
authors.forename: Bernard
authors.initials: B
authors.lastname: Mouillac
authors.forename: Jean
authors.initials: J
authors.lastname: Martinez
authors.forename: Jacky
authors.initials: J
authors.lastname: Marie
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Banères
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D019393:Arrestin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008051:Lipid Bilayers; D011487:Protein Conformation; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D054440:Receptors, Ghrelin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D061987:Sf9 Cells; D018411:Spodoptera
chemical_list: D019393:Arrestin; D008051:Lipid Bilayers; D054440:Receptors, Ghrelin
keywords: 7-Helix Receptor; Arrestin; Dimerization; Fluorescence; G Protein-coupled Receptors (GPCR); G Proteins; Ghrelin; Membrane Proteins