Identification of CXCR4 Domains That Support Coreceptor and Chemokine Receptor Functions

• DOI: 10.1128/jvi.73.4.2752-2761.1999
• Publication Date: 2019-12-31T18:25:21Z
• Authors: Benjamin J. Doranz; Michael J. Orsini; Julie D. Turner; Trevor L. Hoffman; Joanne F. Berson; James A. Hoxie; Stephen C. Peiper; Lawrence F. Brass; Robert W. Doms
• Keywords: 0301 basic medicine; Receptors, CXCR4; 03 medical and health sciences; Molecular Sequence Data; Humans; Amino Acid Sequence; HIV Envelope Protein gp120; Chemokines, CXC; Chemokine CXCL12; Cell Line; Signal Transduction; 3. Good health

The interaction of the chemokine stromal cell-derived factor 1 (SDF-1) with its receptor CXCR4 is vital for cell trafficking during development, capable inhibiting human immunodeficiency virus type (HIV-1) utilization as a coreceptor, and has been implicated in delaying disease progression to AIDS vivo. Because importance this chemokine-chemokine pair both development disease, we investigated molecular basis between ligands SDF-1 HIV-1 envelope. Using chimeras mutants, determined that requires amino terminus binding activates downstream signaling pathways by interacting second extracellular loop CXCR4. SDF-1-mediated activation required Asp-Arg-Tyr motif intracellular CXCR4, was pertussis toxin sensitive, did not require distal C-terminal tail Several mutants were or still supported infection, indicating ability function coreceptor independent signal. Direct studies using X4 gp120s HXB, BH8, MN demonstrated gp120 bind directly specifically CD4-dependent manner, conformationally complex structure on variants support soluble could viral coreceptors, detectable monomeric always predictive function.