Ward Eliot M, Stambach Nicola S, Drickamer Kurt, Taylor Maureen E
Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom.
J Biol Chem. 2006 Jun 2;281(22):15450-6. doi: 10.1074/jbc.M511502200. Epub 2006 Mar 27.
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.
朗格汉斯细胞是一种特殊的皮肤树突状细胞，它摄取并降解抗原，以呈递给免疫系统。朗格素是朗格汉斯细胞的一种细胞表面C型凝集素，可被内化并积聚在伯贝克颗粒中，伯贝克颗粒是朗格汉斯细胞特有的内体循环区室的亚结构域。朗格素结合并介导含甘露糖及相关糖类的糖缀合物的摄取和降解。对人类基因组的分析已鉴定出三种单核苷酸多态性，这些多态性导致朗格素的碳水化合物识别结构域中的氨基酸发生变化。通过表达每种多态形式来检测氨基酸变化对朗格素活性的影响。在成纤维细胞中表达四种常见朗格素单倍型的全长版本，结果显示所有这些形式都能介导新糖蛋白配体的内吞作用。然而，对细胞外结构域片段进行的糖结合试验和差示扫描量热法表明，其中两个氨基酸变化降低了碳水化合物识别结构域对甘露糖的亲和力，并降低了细胞外结构域的稳定性。此外，对含有罕见W264R突变的朗格素进行糖结合分析（该突变先前在一名缺乏伯贝克颗粒的个体中被鉴定出），结果表明这种突变消除了糖结合活性。这些发现表明，某些朗格素单倍型在与病原体的结合方面可能存在差异，因此可能与感染易感性有关。
