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Article
Subject Categories: Signal Transduction
The EMBO Journal (2005) 24, 1954–1964, doi:10.1038/sj.emboj.7600686
Published online 12 May 2005
Glycoprotein hormone receptors: link between receptor homodimerization and negative cooperativity
Eneko Urizar1, 2, Lucia Montanelli1, Tiffany Loy1, Marco Bonomi1, 3, Stéphane Swillens1, Céline Gales4, Michel Bouvier4, Guillaume Smits1, 5, Gilbert Vassart1, 5 and Sabine Costagliola1
1 IRIBHM, Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium
2 Departamento de Neurofarmacología, Facultad de Farmacia, Universidad del País Vasco, Vitoria-Gasteiz, Spain
3 Institute of Endocrine Sciences, Istituto Auxologico Italiano IRCCS and Ospedale Maggiore di Milano IRCCS, Italy
4 Department of Biochemistry, Université de Montréal, succursale Centre-Ville, Montréal, Québec, Canada
5 Service de Génétique Médicale, Hôpital Erasme, Brussels, Belgium

To whom correspondence should be addressed
Sabine Costagliola, IRIBHM, Université Libre de Bruxelles, Campus Erasme, 808 Route de Lennik, 1070 Bruxelles, Belgium. Tel.: +32 2 555 4169; Fax: +32 2 555 4212; E-mail: scostag@ulb.ac.be

Received 3 February 2005; Accepted 27 April 2005; Published online 12 May 2005.
Abstract
The monomeric model of rhodopsin-like G protein-coupled receptors (GPCRs) has progressively yielded the floor to the concept of GPCRs being oligo(di)mers, but the functional correlates of dimerization remain unclear. In this report, dimers of glycoprotein hormone receptors were demonstrated in living cells, with a combination of biophysical (bioluminescence resonance energy transfer and homogenous time resolved fluorescence/fluorescence resonance energy transfer), functional and biochemical approaches. Thyrotropin (TSHr) and lutropin (LH/CGr) receptors form homo- and heterodimers, via interactions involving primarily their heptahelical domains. The large hormone-binding ectodomains were dispensable for dimerization but modulated protomer interaction. Dimerization was not affected by agonist binding. Observed functional complementation indicates that TSHr dimers may function as a single functional unit. Finally, heterologous binding-competition studies, performed with heterodimers between TSHr and LH/CG–TSHr chimeras, demonstrated the unsuspected existence of strong negative cooperativity of hormone binding. Tracer desorption experiments indicated an allosteric behavior in TSHr and, to a lesser extent, in LH/CGr and FSHr homodimers. This study is the first report of homodimerization associated with negative cooperativity in rhodopsin-like GPCRs. As such, it may warrant revisitation of allosterism in the whole GPCR family.
Keywords: allosterism, BRET, GPCR, glycoprotein hormone receptors, oligomerization
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