Molecular uncoupling of C-C chemokine receptor 5-induced chemotaxis and signal transduction from HIV-1 coreceptor activity.
The C-C chemokine receptor 5 (CCR5) plays a crucial role in facilitating the entry of macrophage-tropic strains of the HIV-1 into cells, but the mechanism of this phenomenon is completely unknown. To explore the role of CCR5-derived signal transduction in viral entry, we introduced mutations into two cytoplasmic domains of CCR5 involved in receptor-mediated function. Truncation of the terminal carboxyl-tail to eight amino acids or mutation of the highly conserved aspartate-arginine-tyrosine, or DRY, sequence in the second cytoplasmic loop of CCR5 effectively blocked chemokine-dependent activation of classic second messengers, intracellular calcium fluxes, and the cellular response of chemotaxis. In contrast, none of the mutations altered the ability of CCR5 to act as an HIV-1 coreceptor. We conclude that the initiation of signal transduction, the prototypic function of G protein coupled receptors, is not required for CCR5 to act as a coreceptor for HIV-1 entry into cells.
Gosling
J
J
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94110, USA.
Monteclaro
F S
FS
Atchison
R E
RE
Arai
H
H
Tsou
C L
CL
Goldsmith
M A
MA
Charo
I F
IF
D000595:Amino Acid Sequence; D001665:Binding Sites; D002118:Calcium; D002460:Cell Line; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D003001:Cloning, Molecular; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007668:Kidney; D007700:Kinetics; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism / Q000494:pharmacology*; D008961:Models, Structural; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017433:Protein Structure, Secondary; D019713:Receptors, CCR5; D018121:Receptors, Cytokine / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D015728:Receptors, HIV / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015290:Second Messenger Systems; D017384:Sequence Deletion; D015398:Signal Transduction
D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D018121:Receptors, Cytokine; D015728:Receptors, HIV; D011994:Recombinant Proteins; D002118:Calcium