A Novel Mechanism for Binding of Galactose-terminated Glycans by the C-type Carbohydrate Recognition Domain in Blood Dendritic Cell Antigen 2.
A Novel Mechanism for Binding of Galactose-terminated Glycans by the C-type Carbohydrate Recognition Domain in Blood Dendritic Cell Antigen 2.
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DOI：
10.1074/jbc.m115.660613
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发表时间：
2015-07-03
期刊：
影响因子：
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通讯作者：
Taylor ME
中科院分区：
文献类型：
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作者：
Jégouzo SA;Feinberg H;Dungarwalla T;Drickamer K;Weis WI;Taylor ME
背景：BDCA-2是唯一表达于浆细胞样树突状细胞上的抗炎受体。结果：聚糖阵列和X射线结构分析已被用于确定糖结合BDCA-2的机制。结论：BDCA-2选择性结合Galβ1-3/4GlcNAcβ1- 2 Man。重要性：BDCA-2与IgG或其他血清糖蛋白上不常见的半乳糖终止聚糖的结合提供了调节免疫应答的潜在机制。血液树突状细胞抗原2（BDCA-2;也称为CLEC 4C或CD 303）在浆细胞样树突状细胞上唯一表达。用抗体刺激BDCA-2导致这些细胞中的抗炎反应，但受体的天然配体尚不清楚。BDCA-2细胞外部分的C型碳水化合物识别结构域含有C型动物凝集素的典型特征基序，其结合甘露糖、葡萄糖或GlcNAc，但据报道BDCA-2选择性结合半乳糖封端的双触角N-连接聚糖。已使用聚糖阵列分析和单糖及天然和合成寡糖的结合竞争研究的组合将BDCA-2的结合表位定义为三糖Galβ1-3/4GlcNAcβ1- 2 Man。X射线晶体学和诱变研究表明，甘露糖连接到保守的Ca 2+的主要结合位点，这是C型碳水化合物识别结构域的特征，和GlcNAc和半乳糖残基使额外的相互作用，在一个宽，浅槽相邻的主要结合位点。正如从这些研究中预测的，BDCA-2结合IgG，IgG携带通常不与其他血清糖蛋白连接的半乳糖终止聚糖。因此，BDCA-2有可能作为一个以前未被认识的免疫球蛋白Fc受体。
Background: BDCA-2 is an anti-inflammatory receptor uniquely expressed on plasmacytoid dendritic cells. Results: Glycan arrays and x-ray structural analysis have been used to define the mechanism of sugar binding to BDCA-2. Conclusion: BDCA-2 binds selectively to glycans containing the epitope Galβ1–3/4GlcNAcβ1–2Man. Significance: Binding of BDCA-2 to unusual galactose-terminated glycans on IgG or other serum glycoproteins provides a potential mechanism for modulating the immune response. Blood dendritic cell antigen 2 (BDCA-2; also designated CLEC4C or CD303) is uniquely expressed on plasmacytoid dendritic cells. Stimulation of BDCA-2 with antibodies leads to an anti-inflammatory response in these cells, but the natural ligands for the receptor are not known. The C-type carbohydrate recognition domain in the extracellular portion of BDCA-2 contains a signature motif typical of C-type animal lectins that bind mannose, glucose, or GlcNAc, yet it has been reported that BDCA-2 binds selectively to galactose-terminated, biantennary N-linked glycans. A combination of glycan array analysis and binding competition studies with monosaccharides and natural and synthetic oligosaccharides have been used to define the binding epitope for BDCA-2 as the trisaccharide Galβ1–3/4GlcNAcβ1–2Man. X-ray crystallography and mutagenesis studies show that mannose is ligated to the conserved Ca2+ in the primary binding site that is characteristic of C-type carbohydrate recognition domains, and the GlcNAc and galactose residues make additional interactions in a wide, shallow groove adjacent to the primary binding site. As predicted from these studies, BDCA-2 binds to IgG, which bears galactose-terminated glycans that are not commonly found attached to other serum glycoproteins. Thus, BDCA-2 has the potential to serve as a previously unrecognized immunoglobulin Fc receptor.