Distinct functional sites for human immunodeficiency virus type 1 and stromal cell-derived factor 1α on CXCR4 transmembrane helical domains

Shaomin Tian, Won Tak Choi, Dongxiang Liu, James Pesavento, Youli Wang, Jing An, Joseph G. Sodroski, Ziwei Huang

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

The entry of human immunodeficiency virus type 1 (HIV-1) into the cell is initiated by the interaction of the viral surface envelope protein with two cell surface components of the target cell, CD4 and a chemokine coreceptor, usually CXCR4 or CCR5. The natural ligand of CXCR4 is stromal cell-derived factor 1α (SDF-1α). Whereas the overlap between HIV-1 and SDF-1α functional sites on the extracellular domains of CXCR4 has been well documented, it has yet to be determined whether there are sites in the transmembrane (TM) helices of CXCR4 important for HIV-1 and/or SDF-1α functions, and if such sites do exist, whether they are overlapping or distinctive for the separate functions of CXCR4. For this study, by employing alanine-scanning mutagenesis, 125I-SDF-1α competition binding, Ca2+ mobilization, and cell-cell fusion assays, we found that the mutation of many CXCR4 TM residues, including Tyr45, His79, Asp97, Pro163, Trp252, Tyr255, Asp262, Glu288, His294, and Asn298, could selectively decrease HIV-1-mediated cell fusion but not the binding activity of SDF-1α. Phe87 and Phe292, which were involved in SDF-1α binding, did not play a significant role in the coreceptor activity of CXCR4, further demonstrating the disconnection between physiological and pathological activities of CXCR4 TM domains. Our data also show that four mutations of the second extracellular loop, D182A, DF87A, F189A, and P191A, could reduce HIV-1 entry without impairing either ligand binding or signaling. Taken together, our first detailed characterization of the different functional roles of CXCR4 TM domains may suggest a mechanistic basis for the discovery of new selective anti-HIV agents.

Original languageEnglish (US)
Pages (from-to)12667-12673
Number of pages7
JournalJournal of Virology
Volume79
Issue number20
DOIs
StatePublished - Oct 2005

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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