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Originally published In Press as doi:10.1074/jbc.M205684200 on December 3, 2002

J. Biol. Chem., Vol. 278, Issue 7, 5179-5187, February 14, 2003
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The Core Domain of Chemokines Binds CCR5 Extracellular Domains while Their Amino Terminus Interacts with the Transmembrane Helix Bundle*

Cédric BlanpainDagger §, Benjamin J. Doranz, Antoine BondueDagger , Cédric GovaertsDagger ||, Anne De LeenerDagger , Gilbert VassartDagger **, Robert W. Doms, Amanda ProudfootDagger Dagger , and Marc ParmentierDagger §§¶¶

From the Dagger  Institute of Interdisciplinary Research, ** Service de Génétique Médicale, and §§ Laboratoire de Cytologie et de Cancérologie Experimentale, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070 Brussels, Belgium, the  Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, and the Dagger Dagger  Serono Pharmaceutical Research Institute, Geneva 1228, Switzerland

CCR5 is a functional receptor for various inflammatory CC-chemokines, including macrophage inflammatory protein (MIP)-1alpha and RANTES (regulated on activation normal T cell expressed and secreted), and is the main coreceptor of human immunodeficiency viruses. The second extracellular loop and amino-terminal domain of CCR5 are critical for chemokine binding, whereas the transmembrane helix bundle is involved in receptor activation. Chemokine domains and residues important for CCR5 binding and/or activation have also been identified. However, the precise way by which chemokines interact with and activate CCR5 is presently unknown. In this study, we have compared the binding and functional properties of chemokine variants onto wild-type CCR5 and CCR5 point mutants. Several mutations in CCR5 extracellular domains (E172A, R168A, K191A, and D276A) strongly affected MIP-1alpha binding but had little effect on RANTES binding. However, a MIP/RANTES chimera, containing the MIP-1alpha N terminus and the RANTES core, bound to these mutants with an affinity similar to that of RANTES. Several CCR5 mutants affecting transmembrane helices 2 and 3 (L104F, L104F/F109H/F112Y, F85L/L104F) reduced the potency of MIP-1alpha by 10-100 fold with little effect on activation by RANTES. However, the MIP/RANTES chimera activated these mutants with a potency similar to that of MIP-1alpha . In contrast, LD78beta , a natural MIP-1alpha variant, which, like RANTES, contains a proline at position 2, activated these mutants as well as RANTES. Altogether, these results suggest that the core domains of MIP-1alpha and RANTES bind distinct residues in CCR5 extracellular domains, whereas the N terminus of chemokines mediates receptor activation by interacting with the transmembrane helix bundle.

* This work was supported by the Actions de Recherche Concertées of the Communauté Française de Belgique; the French Agence Nationale de Recherche sur le Syndrome d'Immunodéficience Acquise; the Centre de Recherche Inter-universitaire en Vaccinologie; the Belgian program on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister's Office, Science Policy Programming; the Fonds de la Recherche Scientifique Médicale of Belgium, Télévie; and the Fondation Médicale Reine Elisabeth (to M. P.).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.

§ Aspirant of the Belgian Fonds National de la Recherche Scientifique.

|| Recipient of a FRIA fellowship.

¶¶ To whom correspondence should be addressed: IRIBHN, ULB Campus Erasme, 808 Route de Lennik, B-1070 Brussels, Belgium. Tel.: 32-2-5554171; Fax: 32-2-5554655; E-mail: mparment@ulb.ac.be.

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