Glycosaminoglycans Are Interactants of Langerin: Comparison with gp120 Highlights an Unexpected Calcium-Independent Binding Mode
Glycosaminoglycans Are Interactants of Langerin: Comparison with gp120 Highlights an Unexpected Calcium-Independent Binding Mode
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DOI：
10.1371/journal.pone.0050722
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发表时间：
2012-11-30
期刊：
影响因子：
3.7
通讯作者：
Fieschi, Franck
中科院分区：
文献类型：
--
作者：
Chabrol, Eric;Nurisso, Alessandra;Fieschi, Franck
Langerin是一种在朗格汉斯细胞中特异性表达的C型凝集素。正如最近显示的艾滋病毒，兰热林被认为是捕获病原体和介导其内化到Birbeck颗粒消除。然而，Langerin的确切功能仍然难以捉摸，主要是因为缺乏关于其结合特性和生理配体的信息。基于最近的报告，Langerin结合硫酸化糖，我们在这里进行了比较分析Langerin与富含甘露糖的HIV糖蛋白gp 120和糖胺聚糖（GAG），一个家庭的硫酸化多糖在大多数哺乳动物细胞的表面表达的相互作用。我们的研究结果首次揭示了Langerin通过非常不同的机制与这些不同的聚糖结合，并导致在Langerin中鉴定出一种新的GAG特异性结合模式。与经典的凝集素结构域相反，这个新的结合位点没有表现出Ca 2+依赖性，并且只能在整个三聚体的Langerin胞外结构域中检测到。有趣的是，与GAG的结合并不简单地依赖于净电荷效应，而是依赖于更离散的糖特征，如6-O-硫酸化或艾杜糖醛酸含量。使用分子建模模拟，我们提出了Langerin/肝素复合物的模型，其将GAG结合位点定位在蛋白质的三个碳水化合物识别结构域中的两个的界面处，在α-螺旋卷曲螺旋的边缘处。据我们所知，我们在此强调的Langerin的结合特性以前从未报道过C型凝集素。这些发现为了解Langerin的生物学功能提供了新的见解。
Langerin is a C-type lectin specifically expressed in Langerhans cells. As recently shown for HIV, Langerin is thought to capture pathogens and mediate their internalisation into Birbeck Granules for elimination. However, the precise functions of Langerin remain elusive, mostly because of the lack of information on its binding properties and physiological ligands. Based on recent reports that Langerin binds to sulfated sugars, we conducted here a comparative analysis of Langerin interaction with mannose-rich HIV glycoprotein gp120 and glycosaminoglycan (GAGs), a family of sulfated polysaccharides expressed at the surface of most mammalian cells. Our results first revealed that Langerin bound to these different glycans through very distinct mechanisms and led to the identification of a novel, GAG-specific binding mode within Langerin. In contrast to the canonical lectin domain, this new binding site showed no Ca2+-dependency, and could only be detected in entire, trimeric extracellular domains of Langerin. Interestingly binding to GAGs, did not simply rely on a net charge effect, but rather on more discrete saccharide features, such as 6-O-sulfation, or iduronic acid content. Using molecular modelling simulations, we proposed a model of Langerin/heparin complex, which located the GAG binding site at the interface of two of the three Carbohydrate-recognition domains of the protein, at the edge of the a-helix coiled-coil. To our knowledge, the binding properties that we have highlighted here for Langerin, have never been reported for C-type lectins before. These findings provide new insights towards the understanding of Langerin biological functions.