Activation of CCR5 by chemokines involves an aromatic cluster between transmembrane helices 2 and 3.
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.
Govaerts
Cédric
C
Institut de Recherche Interdisciplinaire en Biologie Humaine et Nucléaire, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070 Bruxelles, Belgium.
Bondue
Antoine
A
Springael
Jean-Yves
JY
Olivella
Mireia
M
Deupi
Xavier
X
Le Poul
Emmanuel
E
Wodak
Shoshana J
SJ
Parmentier
Marc
M
Pardo
Leonardo
L
Blanpain
Cédric
C
D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D008024:Ligands; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D019713:Receptors, CCR5 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D018925:Chemokines; D008024:Ligands; D019713:Receptors, CCR5