Asymmetric conformational changes in a GPCR dimer controlled by G-proteins.
G-protein-coupled receptors (GPCRs) are key players in cell communication. Although long considered as monomeric, it now appears that these heptahelical proteins can form homo- or heterodimers. Here, we analyzed the conformational changes in each subunit of a receptor dimer resulting from agonist binding to either one or both subunits by measuring the fluorescent properties of a leukotriene B(4) receptor dimer with a single 5-hydroxytryptophan-labeled protomer. We show that a receptor dimer with only a single agonist-occupied subunit can trigger G-protein activation. We also show that the two subunits of the receptor dimer in the G-protein-coupled state differ in their conformation, even when both are liganded by the agonist. No such asymmetric conformational changes are observed in the absence of G-protein, indicating that the interaction of the G-protein with the receptor dimer brings specific constraints that prevent a symmetric functioning of this dimer. These data open new options for the differential signaling properties of GPCR dimers.
Damian
Marjorie
M
UMR 5074 CNRS, Laboratoire de Chimie Biomoléculaire et Interactions Biologiques, Faculté de Pharmacie, 17 Avenue Ch. Flahault, 34093 Montpellier Cedex 5, France.
Martin
Aimée
A
Mesnier
Danielle
D
Pin
Jean-Philippe
JP
Banères
Jean-Louis
JL
D019281:Dimerization; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007975:Leukotriene B4 / Q000494:pharmacology; D008024:Ligands; D050505:Mutant Proteins / Q000378:metabolism; D017433:Protein Structure, Secondary / Q000187:drug effects; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism*; D018102:Receptors, Leukotriene B4 / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism*
C513240:LTB4R protein, human; D008024:Ligands; D050505:Mutant Proteins; D021122:Protein Subunits; D043562:Receptors, G-Protein-Coupled; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D020962:Heterotrimeric GTP-Binding Proteins