title: Interdomain movements in metabotropic glutamate receptor activation.
abstract: Many cell surface receptors are multimeric proteins, composed of several structural domains, some involved in ligand recognition, whereas others are responsible for signal transduction. In most cases, the mechanism of how ligand interaction in the extracellular domains leads to the activation of effector domains remains largely unknown. Here we examined how the extracellular ligand binding to the venus flytrap (VFT) domains of the dimeric metabotropic glutamate receptors activate the seven transmembrane (7TM) domains responsible for G protein activation. These two domains are interconnected by a cysteine-rich domain (CRD). We show that any of the four disulfide bridges of the CRD are required for the allosteric coupling between the VFT and the 7TM domains. More importantly, we show that a specific association of the two CRDs corresponds to the active state of the receptor. Indeed, a specific crosslinking of the CRDs with intersubunit disulfide bridges leads to fully constitutively active receptors, no longer activated by agonists nor by allosteric modulators. These data demonstrate that intersubunit movement at the level of the CRDs represents a key step in metabotropic glutamate receptor activation.
authors: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France.
authors: Siluo
authors: S
authors: Huang
authors: Jianhua
authors: J
authors: Cao
authors: Ming
authors: M
authors: Jiang
authors: Gilles
authors: G
authors: Labesse
authors: Jianfeng
authors: J
authors: Liu
authors: Jean-Philippe
authors: JP
authors: Pin
authors: Philippe
authors: P
authors: Rondard
mesh_terms: D000409:Alanine / Q000235:genetics; D000494:Allosteric Regulation; D000818:Animals; D003545:Cysteine / Q000235:genetics; D004220:Disulfides / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009068:Movement; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D004220:Disulfides; D050505:Mutant Proteins; D021122:Protein Subunits; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D003545:Cysteine; D000409:Alanine