Abstract
Langerhans cells are specialized skin dendritic cells that take up and degrade antigens for presentation to the immune system. Langerin, a cell surface C-type lectin of Langerhans cells, can be internalized and accumulates in Birbeck granules, subdomains of the endosomal recycling compartment that are specific to Langerhans cells. Langerin binds and mediates uptake and degradation of glycoconjugates containing mannose and related sugars. Analysis of the human genome has identified three single nucleotide polymorphisms that result in amino acid changes in the carbohydrate-recognition domain of langerin. The effects of the amino acid changes on the activity of langerin were examined by expressing each of the polymorphic forms. Expression of full-length versions of the four common langerin haplotypes in fibroblasts revealed that all of these forms can mediate endocytosis of neoglycoprotein ligands. However, sugar binding assays and differential scanning calorimetry performed on fragments from the extracellular domain showed that two of the amino acid changes reduce the affinity of the carbohydrate-recognition domain for mannose and decrease the stability of the extracellular domain. In addition, analysis of sugar binding by langerin containing the rare W264R mutation, previously identified in an individual lacking Birbeck granules, shows that this mutation abolishes sugar binding activity. These findings suggest that certain langerin haplotypes may differ in their binding to pathogens and thus might be associated with susceptibility to infection.
Highlights
Both the Pro[300] and the Asp[288] forms of langerin would be expected to have decreased ability to interact with glycoconjugates on the surface of microorganisms, the mechanism for the decrease in sugar binding activity is different for the two amino acid changes
Neither of these amino acid changes abolishes the ability of langerin to endocytose a neoglycoprotein ligand, it seems likely that the interactions of langerin with physiological ligands, such as pathogens, would be impaired by these changes
In the case of mannose-binding protein, the single nucleotide polymorphisms result in amino acid changes in the collagenous region of the protein, not in the CRD, and the changes do not affect either the stability or the sugar binding activity of the CRD
Summary
Analysis of sugar binding by langerin containing the rare W264R mutation, previously identified in an individual lacking Birbeck granules, shows that this mutation abolishes sugar binding activity These findings suggest that certain langerin haplotypes may differ in their binding to pathogens and might be associated with susceptibility to infection. Langerin binds glycoconjugates containing mannose and related sugars and is able to mediate uptake and degradation of such ligands (5, 6) These properties may allow langerin to play a role in antigen uptake and processing, the main function of Langerhans cells (7). The results indicate that two of the amino acid changes reduce the stability of langerin and its affinity for mannose, whereas the rare tryptophan to arginine mutation abolishes sugar binding activity
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