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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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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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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DOI: https://doi.org/10.1038/nsmb794