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J. Biol. Chem., Vol. 280, Issue 17, 17135-17141, April 29, 2005

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An Activation Switch in the Rhodopsin Family of G Protein-coupled Receptors

THE THYROTROPIN RECEPTOR^*

Eneko Urizar¶, Sylvie Claeysen, Xavier Deupí||, Cedric Govaerts, Sabine Costagliola, Gilbert Vassart, and Leonardo Pardo||**

From the Institut de Recherche Interdisciplinaire en Biologie Humaine et Nucléaire, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070 Bruxelles, Belgium, the ^||Laboratori de Medicina Computacional, Unitat de Bioestadística and Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain, and the Departamento de Neurofarmacología, Facultad de Farmacia, Universidad del País Vasco, 1006 Vitoria-Gasteiz, Spain

We aimed at understanding molecular events involved in the activation of a member of the G protein-coupled receptor family, the thyrotropin receptor. We have focused on the transmembrane region and in particular on a network of polar interactions between highly conserved residues. Using molecular dynamics simulations and site-directed mutagenesis techniques we have identified residue Asn-7.49, of the NPxxY motif of TM 7, as a molecular switch in the mechanism of thyrotropin receptor (TSHr) activation. Asn-7.49 appears to adopt two different conformations in the inactive and active states. These two states are characterized by specific interactions between this Asn and polar residues in the transmembrane domain. The inactive gauche+ conformation is maintained by interactions with residues Thr-6.43 and Asp-6.44. Mutation of these residues into Ala increases the constitutive activity of the receptor by factors of 14 and 10 relative to wild type TSHr, respectively. Upon receptor activation Asn-7.49 adopts the trans conformation to interact with Asp-2.50 and a putatively charged residue that remains to be identified. In addition, the conserved Leu-2.46 of the (N/S)LxxxD motif also plays a significant role in restraining the receptor in the inactive state because the L2.46A mutation increases constitutive activity by a factor of 13 relative to wild type TSHr. As residues Leu-2.46, Asp-2.50, and Asn-7.49 are strongly conserved, this molecular mechanism of TSHr activation can be extended to other members of the rhodopsin-like family of G protein-coupled receptors.

Received for publication, December 30, 2004 , and in revised form, February 15, 2005.

^* This work was supported by the Belgian State, Prime Minister's office, Service for Sciences, Technology and Culture; the Interuniversity Attraction Poles of the Belgian Federal Office for Scientific, Technical and Cultural Affairs; grants from the FRSM, FNRS, ARBD, and BRAHMS Diagnostics; the European Community Sixth Framework Programme (LSHB-CT-2003-503337); and CICYT (SAF2002-01509). 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.

^¶ Predoctoral fellow from the Government of the Basque Country.

^** To whom correspondence should be addressed: Unitat de Bioestadística, Facultat de Medicina, Edifici M, Campus Universitari, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain. Tel.: 3493-581-2797; Fax: 3493-581-2344; E-mail: Leonardo.Pardo{at}uab.es.

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