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Originally published In Press as doi:10.1074/jbc.M205685200 on October 30, 2002

J. Biol. Chem., Vol. 278, Issue 3, 1892-1903, January 17, 2003
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Activation of CCR5 by Chemokines Involves an Aromatic Cluster between Transmembrane Helices 2 and 3*

Cédric GovaertsDagger §, Antoine BondueDagger , Jean-Yves SpringaelDagger , Mireia Olivella||, Xavier Deupi||, Emmanuel Le Poul**, Shoshana J. WodakDagger Dagger , Marc ParmentierDagger §§, Leonardo Pardo||, and Cédric BlanpainDagger

From the Dagger  Institut de Recherche Interdisciplinaire en Biologie Humaine et Nucléaire, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070 Bruxelles, Belgium, || Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain, ** Euroscreen s.a., B-1070 Brussels, Belgium, and the Dagger Dagger  Service de Conformation des Macromolécules Biologiques, Université Libre de Bruxelles, CP 160/16, Avenue F. Roosevelt, 1050 Bruxelles, Belgium

CCR5 is a G protein-coupled receptor responding to four natural agonists, the chemokines RANTES (regulated on activation normal T cell expressed and secreted), macrophage inflammatory protein (MIP)-1alpha , MIP-1beta , and monocyte chemotactic protein (MCP)-2, and is the main co-receptor for the macrophage-tropic human immunodeficiency virus strains. We have previously identified a structural motif in the second transmembrane helix of CCR5, which plays a crucial role in the mechanism of receptor activation. We now report the specific role of aromatic residues in helices 2 and 3 of CCR5 in this mechanism. Using site-directed mutagenesis and molecular modeling in a combined approach, we demonstrate that a cluster of aromatic residues at the extracellular border of these two helices are involved in chemokine-induced activation. These aromatic residues are involved in interhelical interactions that are key for the conformation of the helices and govern the functional response to chemokines in a ligand-specific manner. We therefore suggest that transmembrane helices 2 and 3 contain important structural elements for the activation mechanism of chemokine receptors, and possibly other related receptors as well.

* This work was supported by the Actions de Recherche Concertées of the Communauté Française de Belgique, the French Agence Nationale de Recherche sur le SIDA, the Centre de Recherche Inter-universitaire en Vaccinologie, the Belgian Programme on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister's Office, Science Policy Programming, the BIOMED and BIOTECH programs of the European Community (Grants BIO4-CT98-0543 and BMH4-CT98-2343), the Fonds de la Recherche Scientifique Médicale of Belgium, Télévie, and the Fondation Médicale Reine Elisabeth (to M. P.). This work was also supported in part by Comisión Interministerial de Ciencia y Tecnología (Spain) Grant SAF2002-01509, a grant from Fundació La Marató TV3, and Improving Human Potential of the European Community Grant HPRI-CT-1999-00071). Computer facilities were provided by the Centre de Computació i Comunicacions de Catalunya.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Current address: Dept. of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143.

These two authors contributed equally to this work.

§§ To whom correspondence should be addressed: IRIBHN, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070 Bruxelles, Belgium. Tel.: 32-2-555-41-71; Fax: 32-2-555-46-55; E-mail: mparment@ulb.ac.be.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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