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J. Biol. Chem., Vol. 280, Issue 11, 9895-9903, March 18, 2005

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Bioluminescence Resonance Energy Transfer Reveals Ligand-induced Conformational Changes in CXCR4 Homo- and Heterodimers^*

Yann Percherancier, Yamina A. Berchiche¶, Isabelle Slight¶, Rudolf Volkmer-Engert||, Hirokazu Tamamura**, Nobutaka Fujii**, Michel Bouvier, and Nikolaus Heveker¶

From the Department of Biochemistry, Université de Montréal, Montréal H3C 3J7, Québéc, Canada, the ^¶Research Centre/Hôpital Sainte-Justine, Montréal, Québec, H3T 1C5, Canada, the ^||Institute for Medical Immunology, Department of Molecular Libraries, Charité-Universitätsmedizin, 10117 Berlin, Germany, and ^**Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan

Homo- and heterodimerization have emerged as prominent features of G-protein-coupled receptors with possible impact on the regulation of their activity. Using a sensitive bioluminescence resonance energy transfer system, we investigated the formation of CXCR4 and CCR2 chemokine receptor dimers. We found that both receptors exist as constitutive homo- and heterodimers and that ligands induce conformational changes within the pre-formed dimers without promoting receptor dimer formation or disassembly. Ligands with different intrinsic efficacies yielded distinct bioluminescence resonance energy transfer modulations, indicating the stabilization of distinct receptor conformations. We also found that peptides derived from the transmembrane domains of CXCR4 inhibited activation of this receptor by blocking the ligand-induced conformational transitions of the dimer. Taken together, our data support a model in which chemokine receptor homo- and heterodimers form spontaneously and respond to ligand binding as units that undergo conformational changes involving both protomers even when only one of the two ligand binding sites is occupied.

Received for publication, September 29, 2004 , and in revised form, December 22, 2004.

^* This work was supported in part by grants from the Canadian Institutes of Health Research (to N. H. and M. B.), the Canadian Foundation for Innovation, and the Fondation de l'Hôpital Sainte Justine. 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.

Supported by the Institut National de la Santé et de la Recherche Médicale (INSERM, France) and the Canadian Institutes of Health Research.

Canada Research Chair in Signal Transduction and Molecular Pharmacology.

Recipient of a scholarship from the Fonds de la Recherche en Santé du Québéc. To whom correspondence should be addressed: Centre de Recherche, 6737 Hôpital Sainte-Justine, 3175 Chemin de la Côte Sainte-Catherine, Montréal, Québec, H3T 1C5, Canada. Tel.: 514-345-4931 (ext. 4190); Fax: 514-345-4801; E-mail: nikolaus.heveker{at}recherche-ste-justine.qc.ca.

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