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J. Biol. Chem., Vol. 283, Issue 24, 16762-16771, June 13, 2008

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The PDZ Protein Mupp1 Promotes G_i Coupling and Signaling of the Mt₁ Melatonin Receptor^*

Jean-Luc Guillaume, Avais M. Daulat¹, Pascal Maurice, Angélique Levoye², Martine Migaud^¶, Lena Brydon³, Benoît Malpaux^¶, Catherine Borg-Capra^||, and Ralf Jockers⁴

From the Institut Cochin, Department of Cell Biology, Université Paris Descartes, CNRS (UMR8104), Paris 75014, France, Inserm U567, Paris 75014, France, ^¶Physiologie de la Reproductionet des Comportements, UMR 6175 INRA-CNRS-Université François Rabelais de Tours-Haras Nationaux, Nouzilly 37380, France, and ^||Hybrigenics, Paris 75014, France

Intracellular signaling events are often organized around PDZ (PSD-95/Drosophila Disc large/ZO-1 homology) domain-containing scaffolding proteins. The ubiquitously expressed multi-PDZ protein MUPP1, which is composed of 13 PDZ domains, has been shown to interact with multiple viral and cellular proteins and to play important roles in receptor targeting and trafficking. In this study, we show that MUPP1 binds to the G protein-coupled MT₁ melatonin receptor and directly regulates its G_i-dependent signal transduction. Structural determinants involved in this interaction are the PDZ10 domain of MUPP1 and the valine of the canonical class III PDZ domain binding motif DSV of the MT₁ carboxyl terminus. This high affinity interaction (K_d 4 nM), which is independent of MT₁ activation, occurs in the ovine pars tuberalis of the pituitary expressing both proteins endogenously. Although the disruption of the MT₁/MUPP1 interaction has no effect on the subcellular localization, trafficking, or degradation of MT₁, it destabilizes the interaction between MT₁ and G_i and abolishes G_i-mediated signaling of MT₁. Our findings highlight a previously unappreciated role of PDZ proteins in promoting G protein coupling to receptors.

Received for publication, March 14, 2008

^* This work was supported by grants from Hybrigenics, the Institut de Recherches SERVIER, the Fondation pour la Recherche Médicale (Equipe FRM), and the Fédération pour la Recherche sur le Cerveau/FRC Neurodon. 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 Fig. S1.

¹ Recipient of an EGIDE fellowship.

² Present address: Institut Pasteur, Laboratoire de Pathogénie Virale Moléculaire, Inserm U819, Dépt. de Virologie, 28 Rue du Dr. Roux, 75724 Paris, France.

³ Present address: University College and Royal Free Medical School, Department of Epidemiology and Public Health, Psychobiology Group, London WC1E 6BT, United Kingdom.

⁴ To whom correspondence should be addressed: Institut Cochin, 22 Rue Méchain, 75014 Paris. Tel.: 331-40-51-64-34; Fax: 331-40-51-64-30; E-mail: jockers{at}cochin.inserm.fr.

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