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
Volume278
Issue3
Pagination1892-903
Date Published2003 Jan 17
ISSN0021-9258
KeywordsAmino 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.

DOI10.1074/jbc.M205685200
Alternate JournalJ. Biol. Chem.
PubMed ID12411445