Abstract
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.
Highlights
Langerin is a receptor in the immune system that binds sugars on pathogens
Protein Expression and Purification—Amino acid changes corresponding to the polymorphisms in the carbohydrate recognition domain (CRD) of human langerin and other mutations were introduced into the human langerin cDNA using synthetic oligonucleotides
A Naturally Occurring Polymorphism in Langerin That Affects Binding to 6SO4-Gal—Several single nucleotide polymorphisms in the human langerin gene that cause nonsynonymous amino acid changes have been reported in the National Center for Biotechnology Information (NCBI) SNP database
Summary
Langerin is a receptor in the immune system that binds sugars on pathogens. Results: The effects of genetic variations that cause changes in the sugar-binding site of human langerin have been investigated. Langerin binds a diverse range of carbohydrates including high mannose structures, fucosylated blood group antigens, and glycans with terminal 6-sulfated galactose. The human langerin gene contains many single nucleotide polymorphisms (SNPs) including some that cause amino acid changes in the CRD and affect sugar binding activity [22]. The studies described here characterize the effects of a polymorphism that changes Lys-313, one of the amino acid residues critical for binding 6SO4-Gal-terminating glycans, to isoleucine, which is linked to another SNP that changes Asn-288 to Asp. A combination of mutagenesis, glycan array screening, and structural studies shows that the K313I change alters the specificity of langerin for glycans in an unexpected way, abolishing binding to 6SO4-Gal-containing ligands, and causing enhanced binding to glycans with terminal GlcNAc
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