Allosteric regulation of CCR5 by guanine nucleotides and HIV-1 envelope.
The chemokine receptor CCR5 is the principal coreceptor for R5 (macrophage-tropic) strains of HIV-1. CCR5 uses G-proteins as transducing elements. Here we report the biochemical consequences of the interaction between CCR5 and G-proteins. Macrophage inflammatory protein-1beta (MIP-1beta) binding to CCR5 was potently and specifically inhibited by guanine nucleotides. The molecular mechanism of this inhibitory effect was shown to be a dose-dependent reduction in MIP-1beta receptors. We also show that the MIP-1beta binding site is allosterically regulated by monovalent cations and that binding of this endogenous agonist is highly temperature sensitive and dependent on divalent cations, characteristic of a G-protein-coupled receptor(GPCR). HIV-1 envelope glycoprotein decreased the affinity of CCR5 for MIP-1beta but also altered the kinetics of MIP-1beta binding to CCR5, proving that it interacts with a distinct, but allosterically coupled binding site. The findings described herein contribute to our understanding of how CCR5 interacts with chemokines and HIV-1 envelope.
Staudinger
R
R
Department of Neurology, New York University School of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
Wang
X
X
Bandrés
J C
JC
D000494:Allosteric Regulation; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D054407:Chemokine CCL4; D006224:Cricetinae; D019204:GTP-Binding Proteins / Q000378:metabolism; D006150:Guanine Nucleotides / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D011485:Protein Binding; D019713:Receptors, CCR5 / Q000378:metabolism*; D013696:Temperature
D015704:CD4 Antigens; D054407:Chemokine CCL4; D006150:Guanine Nucleotides; D015699:HIV Envelope Protein gp120; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D019204:GTP-Binding Proteins