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.
Highlights
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
When the carbohydrate-recognition domain (CRD) 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
This information suggests that DC-SIGN and DC-SIGNR employ a novel mechanism of carbohydrate recognition to achieve specificity for their natural ligands by binding multiple high mannose oligosaccharides spaced at appropriate distances on the surface of a limited number of glycoproteins
Summary
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 extracellular domain of each consists of a series of seven and a half tandem repeats of a highly conserved sequence of 23 amino acids followed by a C-terminal C-type carbohydrate recognition domain (CRD) Both ICAM-3 and gp120 carry an abundance of N-linked high mannose oligosaccharides. Soluble recombinant fragments of DC-SIGN and DC-SIGNR have been used to demonstrate that the extracellular domain of each molecule is a tetramer stabilized by an ␣-helical neck and that the individual CRDs possess high affinity for mannose-containing oligosaccharides This information suggests that DC-SIGN and DC-SIGNR employ a novel mechanism of carbohydrate recognition to achieve specificity for their natural ligands by binding multiple high mannose oligosaccharides spaced at appropriate distances on the surface of a limited number of glycoproteins
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