DC-SIGN Binds to HIV-1 Glycoprotein 120 in a Distinct but Overlapping Fashion Compared with ICAM-2 and ICAM-3

Stephen V. Su, Patrick Hong, Sarah Baik, Oscar A. Negrete, Kevin B. Gurney, Benhur Lee

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

DC-SIGN is a C-type lectin that binds to endogenous adhesion molecules ICAM-2 and ICAM-3 as well as the viral envelope glycoprotein human immunodeficiency virus, type 1, glycoprotein (gp) 120. We wished to determine whether DC-SIGN binds differently to its endogenous ligands ICAM-2 and ICAM-3 versus HIV-1 gp120. We found that recombinant soluble DC-SIGN bound to gp120-Fc more than 100- and 50-fold better than ICAM-2-Fc and ICAM-3-Fc, respectively. This relative difference was maintained using DC-SIGN expressed on three different CD4-negative cell lines. Although the cell surface affinity for gp120 varied by up to 4-fold on the cell lines examined, the affinity for gp120 was not a correlate of the ability of the cell line to transfer virus. Monosaccharides with equatorial 4-OH groups competed as well as D-mannose for gp120 binding to DC-SIGN, regardless of how the other hydroxyl groups were positioned. Disaccharide competitors and glycan chip analysis showed that DC-SIGN has a preference for oligosaccharides linked in an α-anomeric configuration. Alanine-scanning mutagenesis of DC-SIGN revealed that highly conserved residues that coordinate calcium (Asp-366) and/or are involved in both calcium and specific carbohydrate interactions (Glu-347, Asn-349, Glu-354, and Asp-355) significantly compromised binding to all three ligands. Mutating non-conserved residues (Asn-311, Arg-345, Val-351, Gly-352, Glu-353, Ser-360, Gly-361, and Asn-362) minimally affected binding except for the Asp-367 mutant, which enhanced gp120 binding but diminished ICAM-2 and ICAM-3 binding. Conversely, mutat-ing the moderately conserved residue (Gly-346) abrogated gp120 binding but enhanced ICAM-2 and ICAM-3 binding. Thus, DC-SIGN appears to bind in a distinct but overlap-ping manner to gp120 when compared with ICAM-2 and ICAM-3.

Original languageEnglish
Pages (from-to)19122-19132
Number of pages11
JournalJournal of Biological Chemistry
Volume279
Issue number18
DOIs
StatePublished - 30 Apr 2004
Externally publishedYes

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