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Activation of CCR5 by chemokines involves an aromatic cluster between transmembrane helices 2 and 3

par Govaerts, Cédric ;Bondue, Antoine ;Springael, Jean-Yves ;Olivella, Mireia;Deupi, Xavier;Le Poul, Emmanuel;Wodak, Shoshana ;Parmentier, Marc ;Pardo, Leonardo;Blanpain, Cédric
Référence The Journal of biological chemistry, 278, 3, page (1892-1903)
Publication Publié, 2003-01

Article révisé par les pairs

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Résumé :

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)-1 alpha, MIP-1 beta, 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.