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J. Biol. Chem., Vol. 281, Issue 34, 24653-24661, August 25, 2006

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

Philippe Rondard¹², Jianfeng Liu, Supported by the National Natural Science Foundation of China (Grants 30530820, 30470368, and 30100092)¹³, Siluo Huang, Fanny Malhaire, Claire Vol, Alexia Pinault, Gilles Labesse^¶, and Jean-Philippe Pin

From the CNRS Unité Mixte de Recherche 5203, INSERM U661, Universités Montpellier 1 and 2, and Institut de Génomique Fonctionnelle, Département de Pharmacologie Moléculaire, 141 Rue de la Cardonille, Montpellier F-34094, France, Institute of Biophysics and Biochemistry, Huazhong University of Science and Technology, 1037 Luoyu Avenue, 430074 Wuhan, Hubei, China, and ^¶Plate-forme RIO de Biologie Structurale, Centre de Biochimie Structurale, INSERM U414, CNRS Unité Mixte de Recherche 5048, Université Montpellier 1, 15 Avenue Charles Flahault, Montpellier F-34060, France

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.

Received for publication, March 10, 2006 , and in revised form, June 16, 2006.

^* This work was supported in part by grants from the CNRS, INSERM, Universités de Montpellier 1 and 2, the Action Concertée Incitative "Biologie Cellulaire, Moléculaire et Structurale" of the French Ministry of Research and Technology (BCMS328), the European Community (LSHB-CT-200-503337), the Fondation de France "Comité Parkinson", the Agence Nationale pour la Recherche (ANR-05-NEUR-0121-04), and Addex Pharmaceuticals (Genève, Switzerland). Senomyx (La Jolla, CA) is also acknowledged for its unrestricted support. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Both authors contributed equally to this work.

² To whom correspondence may be addressed. Tel.: 33-4-67-14-29-66; Fax: 33-4-67-54-24-32; E-mail: prondard{at}igf.cnrs.fr. ³ To whom correspondence may be addressed. Tel.: 86-27-87792031; Fax: 87792024; E-mail: jfliu{at}mail.hust.edu.cn.

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