Identification of residues of CXCR4 critical for human immunodeficiency virus coreceptor and chemokine receptor activities

Citation
A. Brelot et al., Identification of residues of CXCR4 critical for human immunodeficiency virus coreceptor and chemokine receptor activities, J BIOL CHEM, 275(31), 2000, pp. 23736-23744
Citations number
61
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
275
Issue
31
Year of publication
2000
Pages
23736 - 23744
Database
ISI
SICI code
0021-9258(20000804)275:31<23736:IOROCC>2.0.ZU;2-U
Abstract
CXCR4 is a G-coupled receptor for the stromal cell-derived factor (SDF-1) c hemokine, and a CD4-associated human immunodeficiency virus type 1 (HIV-1) coreceptor. These functions were studied in a panel of CXCR4 mutants bearin g deletions in the NH2-terminal extracellular domain (NT) or substitutions in the NT, the extracellular loops (ECL), or the transmembrane domains (TMs ). The coreceptor activity of CXCR4 was markedly impaired by mutations of t wo Tyr residues in NT (Y7A/ Y12A) or at a single Asp residue in ECL2 (D193A ), ECL3 (D262A), or TMII (D97N). These acidic residues could engage electro statical interactions with basic residues of the HIV-1 envelope protein gp1 20, known to contribute to the selectivity for CXCR4. The ability of CXCR4 mutants to bind SDF-1 and mediate cell signal was consistent with the two-s ite model of chemokine-receptor interaction. Site I involved in SDF-1 bindi ng but not signaling was located in NT with particular importance of Glu(14 ) and/or Glu(15) and Tyr(21). Residues required for both SDF-1 binding and signaling, and thus probably part of site II, were identified in ECL2 (Asp( 187)), TMII (Asp(97)), and TMVII (Glu(288)). The first residues (2-9) of NT also seem required for SDF-1 binding and signaling. A deletion in the thir d intracellular loop abolished signaling, probably by disrupting the coupli ng with G proteins. The identification of CXCR4 residues involved in the in teraction with both SDF-1 and HIV-1 may account for the signaling activity of gp120 and has implications for the development of antiviral compounds.