A novel mechanism of carbohydrate recognition by the C-type lectins DC-SIGN and DC-SIGNR. Subunit organization and binding to multivalent ligands

• Published in: The Journal of biological chemistry Vol. 276; no. 31; pp. 28939 - 28945
• Main Authors: Mitchell, D A, Fadden, A J, Drickamer, K
• Format: Journal Article
• Language: English
• Published: United States 03.08.2001
• Subjects: Amino Acid Sequence; Base Sequence; Binding Sites; Carbohydrate Metabolism; Carbohydrate Sequence; Cell Adhesion Molecules; Cross-Linking Reagents; Dimerization; Glycolipids - metabolism; Glycopeptides - metabolism; HIV-1 - physiology; Humans; Kinetics; Lectins - chemistry; Lectins - genetics; Lectins - metabolism; Lectins, C-Type; Ligands; Macromolecular Substances; Mannose - metabolism; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; Molecular Sequence Data; Monosaccharides - metabolism; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Oligosaccharides - metabolism; Peptide Fragments - chemistry; Peptide Fragments - isolation & purification; Peptide Fragments - metabolism; Protein Conformation; Protein Structure, Secondary; Protein Subunits; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M104565200

DC-SIGN and DC-SIGNR are cell-surface receptors that mediate cell-cell interactions within the immune system by binding to intercellular adhesion molecule-3. The receptor polypeptides share 77% amino acid sequence identity and are type II transmembrane proteins. The extracellular domain of each comprises seven 23-residue tandem repeats and a C-terminal C-type carbohydrate-recognition domain (CRD). Cross-linking, equilibrium ultracentrifugation, and circular dichroism studies of soluble recombinant fragments of DC-SIGN and DC-SIGNR have been used to show that the extracellular domain of each receptor is a tetramer stabilized by an alpha-helical stalk. Both DC-SIGN and DC-SIGNR bind ligands bearing mannose and related sugars through the CRDs. The CRDs of DC-SIGN and DC-SIGNR bind Man(9)GlcNAc(2) oligosaccharide 130- and 17-fold more tightly than mannose, and affinity for a glycopeptide bearing two such oligosaccharides is increased by a further factor of 5- to 25-fold. These results indicate that the CRDs contain extended or secondary oligosaccharide binding sites that accommodate mammalian-type glycan structures. When the CRDs are clustered in the tetrameric extracellular domain, their arrangement provides a means of amplifying specificity for multiple glycans on host molecules targeted by DC-SIGN and DC-SIGNR. Binding to clustered oligosaccharides may also explain the interaction of these receptors with the gp120 envelope protein of human immunodeficiency virus-1, which contributes to virus infection.