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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Constitutively Active CCR5 Chemokine Receptors Differ in Mediating HIV Envelope-dependent Fusion
PLoS ONE, Volume 8, No. 1, Article e54532, Year 2013
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Description
The CCR5 chemokine receptor is a rhodopsin-like G protein-coupled receptor that mediates the effects of pro-inflammatory β-chemokines. CCR5 is also the major co-receptor for entry of human immunodeficiency virus (HIV) into human cells. G protein-coupled receptors exist in ensembles of active and inactive conformations. Active receptor conformations can be stabilized by mutations. Although binding of the HIV envelope protein to CCR5 stimulates cellular signaling, the CCR5 conformation that induces fusion of the viral membrane with cellular membranes is not known. We mutated conserved amino acids to generate constitutively active CCR5 receptors, which are stabilized in active conformations, and tested the ability of constitutively active CCR5 receptors to mediate HIV envelope-directed membrane fusion. Mutation of the Asp3.49(125) and Arg6.32(225) residues of CCR5 did not cause constitutive activity, but Lys or Pro substitutions for Thr2.56(82), in the TxP motif, caused high basal inositol phosphate signaling. Signaling did not increase in response to MIP-1β, suggesting that the Thr2.56(82) mutants were fully stabilized in active conformations. The Thr2.56(82)Lys mutation severely decreased cell surface CCR5 expression. Combining the Thr2.56(82)Lys mutation with an Arg6.32(225)Gln mutation partially reversed the decrease in expression. Mutants with Thr2.56(82)Lys substitutions were poor mediators of HIV envelope-directed membrane fusion, but mutants with the Thr2.65(82)Pro substitution exhibited full co-receptor function. Our results suggest that the Thr2.65(82)Lys and Thr2.65(82)Pro mutations stabilize distinct constitutively active CCR5 conformations. Lys in position 2.65(82) stabilizes activated receptor conformations that appear to be constitutively internalized and do not induce envelope-dependent membrane fusion, whereas Pro stabilizes activated conformations that are not constitutively internalized and fully mediate envelope-directed membrane fusion. © 2013 de Voux et al.
Authors & Co-Authors
de Voux, Alex
South Africa, Cape Town
Faculty of Health Sciences
United States, Atlanta
Rollins School of Public Health
Chan, Mei Chi
South Africa, Cape Town
Faculty of Health Sciences
Folefoc, Asongna T.
South Africa, Cape Town
Faculty of Health Sciences
Canada, Calgary
University of Calgary
Madziva, Michael Taurai
South Africa, Johannesburg
University of the Witwatersrand
Flanagan, Colleen A.
South Africa, Johannesburg
University of the Witwatersrand
Statistics
Citations: 15
Authors: 5
Affiliations: 4
Identifiers
Doi:
10.1371/journal.pone.0054532
e-ISSN:
19326203
Research Areas
Cancer
Infectious Diseases