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

TitleActivation of CCR5 by chemokines involves an aromatic cluster between transmembrane helices 2 and 3.
Publication TypeJournal Article
Year of Publication2003
AuthorsGovaerts, C., Bondue A., Springael J-Y., Olivella M., Deupi X., Le Poul E., Wodak S. J., Parmentier M., Pardo L., and Blanpain C.
JournalJ Biol Chem
Date Published2003 Jan 17
KeywordsAmino Acid Sequence, Cell Membrane, Chemokines, Ligands, Molecular Sequence Data, Protein Binding, Protein Conformation, Receptors, CCR5, Sequence Homology, Amino Acid

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.

Alternate JournalJ. Biol. Chem.
PubMed ID12411445