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Regulation of C-C chemokine receptor 5 (CCR5) stability by Lys and by transmembrane protein aptamers that target it for lysosomal degradation. | LitMetric

AI Article Synopsis

Article Abstract

C-C motif chemokine receptor 5 (CCR5) is a cell surface-associated, immune-regulatory G protein-coupled receptor (GCPR) with seven transmembrane helices. We previously reported the isolation and initial characterization of short artificial transmembrane protein aptamers, named "traptamers," that specifically down-regulate CCR5 expression and inhibit infection of human T cells by HIV strains that use CCR5 as a co-receptor. Here, we investigated the mechanism of traptamer-mediated CCR5 down-regulation and show that most of the traptamers (designated class 1 traptamers) form a stable complex with CCR5 and target it for lysosome-mediated degradation. The ability of these traptamers to down-regulate CCR5 depended on Lys in the fifth transmembrane helix of CCR5. In the absence of traptamers, substitution of Lys to an uncharged amino acid increased CCR5 stability, and introduction of a lysine at the homologous position in CCR2b, a related chemokine receptor, decreased CCR2b levels. The prototypic class 2 traptamer BY6M4 also formed a complex with CCR5, but CCR5 down-regulation caused by class 2 traptamers did not depend on the lysosome or on Lys These results demonstrate that traptamers use diverse mechanisms to down-regulate CCR5 and identify a specific amino acid that plays a central role in controlling chemokine receptor stability. Further studies of these traptamers are likely to provide new insights into CCR5 metabolism and biology and may suggest new therapeutic approaches to modulate the levels of CCR5 and other GPCRs.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995508PMC
http://dx.doi.org/10.1074/jbc.RA117.001067DOI Listing

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