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

Nature Structural & Molecular Biology volume 11, pages 706–713 (2004)Cite this article

Abstract

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 mGlu1 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.

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Figure 1: Different conformations of the mGlu1 VFT dimer determined by X-ray crystallography.
Figure 2: Cellular localization and function of mG5C1 and mG5C2 chimeras.
Figure 3: Dimerization of mG5C1 and mG5C2 chimeras at the cell surface.
Figure 4: Mutation of the mGlu5 binding site.
Figure 5: Biphasic dose-response curves of 'heterodimeric' mGlu5 receptor.
Figure 6: Active efficacy of the Aco conformation of the dimer of VFTs.
Figure 7: Cis- and trans-activation in mGlu receptors.
Figure 8: Comparison of the active efficacy of Aco and Acc conformations.

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Acknowledgements

We thank V. Binet, C. Goudet, P. Rondard (Montpellier), C. Hatton, J. Neyton and P. Paoletti (Paris) for constructive discussions and critical reading of manuscript. We also to thank Cis Bio International Research group for the supply of labeled antibodies, and G. Mathis and E. Trinquet from Cis Bio International for their strong support. This work was supported by grants from the Centre National de Recherche Scientifique (CNRS), the action initiative Molécules et Cibles Thérapeutiques from Institut National de la Santé et de la Recherche Médicale, CNRS and the French government, Addex Pharmaceuticals, Fondation Paul Hamel, Comité Parkinson of the Fondation de France and the European Community (grant LSHB-CT-200-503337). J.K. was supported by a CNRS fellowship.

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  1. Anne-Sophie Bessis

    Present address: Addex Pharmaceuticals SA, 12, Chemin Des Aulx, CH-1228, Plan les Ouates, Geneva, Switzerland

Authors and Affiliations

  1. Department of Molecular Pharmacology, Laboratory of Functional Genomics, Centre National de la Recherche Scientifique, Unite Propre de Recherche 2580, 141 rue de la Cardonille, Montpellier, 34094 Cedex 5, France

    Julie Kniazeff, Anne-Sophie Bessis, Damien Maurel, Laurent Prézeau & Jean-Philippe Pin

  2. Cis Bio International, BP 175, Bagnols sur Ceze, F 30203, France

    Damien Maurel & Hervé Ansanay

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Correspondence to Jean-Philippe Pin.

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Kniazeff, J., Bessis, AS., Maurel, D. et al. Closed state of both binding domains of homodimeric mGlu receptors is required for full activity. Nat Struct Mol Biol 11, 706–713 (2004). https://doi.org/10.1038/nsmb794

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