Title | Activation of CCR5 by chemokines involves an aromatic cluster between transmembrane helices 2 and 3. |
Publication Type | Journal Article |
Year of Publication | 2003 |
Authors | Govaerts, C., A. Bondue, J-Y. Springael, M. Olivella, X. Deupi, E. Le Poul, S. J. Wodak, M. Parmentier, L. Pardo, and C. Blanpain |
Journal | J Biol Chem |
Volume | 278 |
Issue | 3 |
Pagination | 1892-903 |
Date Published | 2003 Jan 17 |
ISSN | 0021-9258 |
Keywords | Amino Acid Sequence, Cell Membrane, Chemokines, Ligands, Molecular Sequence Data, Protein Binding, Protein Conformation, Receptors, CCR5, Sequence Homology, Amino Acid |
Abstract | 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. |
DOI | 10.1074/jbc.M205685200 |
Alternate Journal | J. Biol. Chem. |
PubMed ID | 12411445 |
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