Closed state of both binding domains of homodimeric mGlu receptors is required for full activity.

Julie Kniazeff (1) , Anne-Sophie Bessis (1) , Damien Maurel (2) , Hervé Ansanay (2) , Laurent Prézeau (1) , Jean-Philippe Pin (1)

1 IGF - Institut de Génomique Fonctionnelle
2 HTRF - Homogeneous Time-resolved Fluorescence

Membrane receptors, key components in signal transduction, often function as dimers. These include some G protein-coupled receptors such as metabotropic glutamate (mGlu) receptors that have large extracellular domains (ECDs) where agonists bind. How agonist binding in dimeric ECDs activates the effector domains remains largely unknown. The structure of the dimeric ECDs of mGlu(1) solved in the presence of agonist revealed two specific conformations in which either one or both protomers are in an agonist-stabilized closed form. Here we examined whether both conformations correspond to an active form of the full-length receptor. Using a system that allows the formation of dimers made of a wild-type and a mutant subunit, we show that the closure of one ECD per dimer is sufficient to activate the receptor, but the closure of both ECDs is required for full activity.

Mots clés: GPCR; GABAB; dimerization

Domaines: Neurobiologie; Pharmacologie

Julie Kniazeff, Anne-Sophie Bessis, Damien Maurel, Hervé Ansanay, Laurent Prézeau, et al.. Closed state of both binding domains of homodimeric mGlu receptors is required for full activity.. Nature Structural and Molecular Biology, 2004, 11 (8), pp.706-13. ⟨10.1038/nsmb794⟩. ⟨hal-00318999⟩