Coupling of Agonist Binding to Effector Domain Activation in Metabotropic Glutamate-like Receptors

Abstract

Many membrane receptors are made of a ligand binding domain and an effector domain mediating intracellular signaling. This is the case for the metabotropic glutamate-like G-protein-coupled receptors. How ligand binding leads to the active conformation of the effector domain in such receptors is largely unknown. Here, we used an evolutionary trace analysis and mutagenesis to identify critical residues involved in the allosteric coupling between the Venus flytrap ligand binding domain (VFT) and the heptahelical G-protein activating domain of the metabotropic glutamate-like receptors. We have shown that a conserved interdomain disulfide bridge is required for this allosteric interaction. Taking into account that these receptors are homodimers, this finding provides important new information explaining how the different conformations of the dimer of VFT lead to different signaling of such dimeric receptors. Many membrane receptors are made of a ligand binding domain and an effector domain mediating intracellular signaling. This is the case for the metabotropic glutamate-like G-protein-coupled receptors. How ligand binding leads to the active conformation of the effector domain in such receptors is largely unknown. Here, we used an evolutionary trace analysis and mutagenesis to identify critical residues involved in the allosteric coupling between the Venus flytrap ligand binding domain (VFT) and the heptahelical G-protein activating domain of the metabotropic glutamate-like receptors. We have shown that a conserved interdomain disulfide bridge is required for this allosteric interaction. Taking into account that these receptors are homodimers, this finding provides important new information explaining how the different conformations of the dimer of VFT lead to different signaling of such dimeric receptors. Many cell surface receptors are composed of multiple domains, one being involved in ligand recognition and another in signal transduction. Understanding how ligand binding leads to the activation of the effector domain is an important issue. Recently, models have been proposed for the coupling between ligand binding and channel opening in the GABAA and nicotinic receptors (1Kash T.L. Jenkins A. Kelley J.C. Trudell J.R. Harrison N.L. Nature. 2003; 421: 272-275Crossref PubMed Scopus (280) Google Scholar, 2Bouzat C. Gumilar F. Spitzmaul G. Wang H.-L. Rayes D. Hansen S.B. Taylor Nature. PubMed Scopus Google Scholar, Nature. 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