title: A novel mechanism of carbohydrate recognition by the C-type lectins DC-SIGN and DC-SIGNR. Subunit organization and binding to multivalent ligands.
abstract: 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.
authors.affiliation: Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom.
authors.forename: D A
authors.initials: DA
authors.lastname: Mitchell
authors.forename: A J
authors.initials: AJ
authors.lastname: Fadden
authors.forename: K
authors.initials: K
authors.lastname: Drickamer
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D050260:Carbohydrate Metabolism; D002240:Carbohydrate Sequence; D015815:Cell Adhesion Molecules; D003432:Cross-Linking Reagents; D019281:Dimerization; D006017:Glycolipids / Q000378:metabolism; D006020:Glycopeptides / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D007700:Kinetics; D037102:Lectins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D037181:Lectins, C-Type; D008024:Ligands; D046911:Macromolecular Substances; D008358:Mannose / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009005:Monosaccharides / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009844:Oligosaccharides / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D021122:Protein Subunits; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D003432:Cross-Linking Reagents; D006017:Glycolipids; D006020:Glycopeptides; D037102:Lectins; D037181:Lectins, C-Type; D008024:Ligands; D046911:Macromolecular Substances; D008358:Mannose; D008565:Membrane Proteins; D009005:Monosaccharides; D009419:Nerve Tissue Proteins; D009844:Oligosaccharides; D010446:Peptide Fragments; D021122:Protein Subunits; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C433029:CLEC4M protein, human