Common polymorphisms in human langerin change specificity for glycan ligands.
Langerin, a C-type lectin on Langerhans cells, mediates carbohydrate-dependent uptake of pathogens in the first step of antigen presentation to the adaptive immune system. Langerin binds a diverse range of carbohydrates including high mannose structures, fucosylated blood group antigens, and glycans with terminal 6-sulfated galactose. Mutagenesis and quantitative binding assays indicate that salt bridges between the sulfate group and two lysine residues compensate for the nonoptimal binding of galactose at the primary Ca(2+) site. A commonly occurring single nucleotide polymorphism (SNP) in human langerin results in change of one of these lysine residues, Lys-313, to isoleucine. Glycan array screening reveals that this amino acid change abolishes binding to oligosaccharides with terminal 6SO4-Gal and enhances binding to oligosaccharides with terminal GlcNAc residues. Structural analysis shows that enhanced binding to GlcNAc may result from Ile-313 packing against the N-acetyl group. The K313I polymorphism is tightly linked to another SNP that results in the change N288D, which reduces affinity for glycan ligands by destabilizing the Ca(2+)-binding site. Langerin with Asp-288 and Ile-313 shows no binding to 6SO4-Gal-terminated glycans and increased binding to GlcNAc-terminated structures, but overall decreased binding to glycans. Altered langerin function in individuals with the linked N288D and K313I polymorphisms may affect susceptibility to infection by microorganisms.
From the Department of Life Sciences, Imperial College, London SW7 2AZ, United Kingdom and.
Hadar
H
Feinberg
Thomas J W
TJ
Rowntree
Shawn L W
SL
Tan
Kurt
K
Drickamer
William I
WI
Weis
Maureen E
ME
Taylor
D019943:Amino Acid Substitution; D015703:Antigens, CD / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D018360:Crystallography, X-Ray; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007239:Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D037241:Mannose-Binding Lectins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009844:Oligosaccharides / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary
D015703:Antigens, CD; C121916:CD207 protein, human; D037181:Lectins, C-Type; D008024:Ligands; D037241:Mannose-Binding Lectins; D009844:Oligosaccharides; D002118:Calcium
CD207; Carbohydrate-binding Protein; Crystal Structure; Genetic Polymorphism; Glycobiology; Lectin; Sulfated Glycans