Abstract
The dendritic cell-specific C-type lectin DC-SIGN functions as a pathogen receptor that recognizes Schistosoma mansoni egg antigens through its major glycan epitope Galbeta1,4(Fucalpha1,3)GlcNAc (Lex). Here we report that L-SIGN, a highly related homologue of DC-SIGN found on liver sinusoidal endothelial cells, binds to S. mansoni egg antigens but not to the Lex epitope. L-SIGN does bind the Lewis antigens Lea, Leb, and Ley, similar as DC-SIGN. A specific mutation in the carbohydrate recognition domain of DC-SIGN (V351G) abrogates binding to all Lewis antigens. In L-SIGN Ser363 is present at the corresponding position of Val351 in DC-SIGN. Replacement of this Ser into Val resulted in a "gain of function" L-SIGN mutant that binds to Lex, and shows increased binding to the other Lewis antigens. These data indicate that Val351 is important for the fucose specificity of DC-SIGN. Molecular modeling and docking of the different Lewis antigens in the carbohydrate recognition domains of L-SIGN, DC-SIGN, and their mutant forms, demonstrate that Val351 in DC-SIGN creates a hydrophobic pocket that strongly interacts with the Fucalpha1,3/4-GlcNAc moiety of the Lewis antigens. The equivalent amino acid residue Ser363 in L-SIGN creates a hydrophilic pocket that prevents interaction with Fucalpha1,3-GlcNAc in Lex but supports interactions with the Fucalpha1,4-GlcNAc moiety in Lea and Leb antigens. These data demonstrate for the first time that DC-SIGN and L-SIGN differ in their carbohydrate binding profiles and will contribute to our understanding of the functional roles of these C-type lectin receptors, both in recognition of pathogen and self-glycan antigens.
Original language | English |
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Pages (from-to) | 33161-7 |
Number of pages | 7 |
Journal | Journal of Biological Chemistry |
Volume | 279 |
Issue number | 32 |
DOIs | |
Publication status | Published - 6 Aug 2004 |
Keywords
- Amino Acid Sequence
- Animals
- Antigens, Helminth/metabolism
- Binding Sites
- Cell Adhesion Molecules/chemistry
- Endothelial Cells/chemistry
- Fucose/metabolism
- Humans
- Lectins, C-Type/chemistry
- Lewis X Antigen/metabolism
- Liver/chemistry
- Models, Molecular
- Molecular Sequence Data
- Molecular Structure
- Mutagenesis, Site-Directed
- Oligosaccharides/metabolism
- Ovum/immunology
- Receptors, Cell Surface/chemistry
- Schistosoma mansoni/immunology
- Serine/chemistry
- Structure-Activity Relationship
- Transfection
- Valine/chemistry