Mechanism of pathogen recognition by human dectin-2.
Mechanism of pathogen recognition by human dectin-2.
复制标题
DOI：
10.1074/jbc.m117.799080
复制
发表时间：
2017-08-11
期刊：
影响因子：
--
通讯作者：
Taylor ME
中科院分区：
文献类型：
--
作者：
Feinberg H;Jégouzo SAF;Rex MJ;Drickamer K;Weis WI;Taylor ME
Dectin-2是巨噬细胞和先天免疫系统的其他细胞上的C型凝集素，其功能是响应病原体，特别是真菌。dectin-2中的碳水化合物识别结构域（CRD）连接到与常见Fc受体γ亚基相互作用以启动免疫信号传导的跨膜序列。通过表征在细菌系统中表达的CRD，已经研究了dectin-2选择性结合病原体的分子机制。竞争结合研究表明，CRD与单糖的结合亲和力适中，甘露糖连接的α1-2或α1-4与第二个甘露糖残基的亲和力大大增强。聚糖阵列分析证实了CRD与含有Manα1- 2 Man表位的聚糖的选择性结合。CRD晶体与一种葡聚糖型高甘露糖Man 9 GlcNAc 2寡糖复合后，在聚糖的两个不同末端与Manα1- 2 Man发生相互作用，其中还原性末端甘露糖残基在一级结合位点与Ca 2+连接，非还原性末端甘露糖残基占据相邻的二级位点。比较DC-SIGN和langerin（先天免疫系统的另外两种病原体结合受体）中的结合位点，揭示了为什么这两个结合位点仅容纳末端Manα1- 2 Man结构，而dectin-2可以在甘露聚糖和其他多糖的内部位置结合Manα1- 2 Man。dectin-2结合位点的特异性和几何结构提供了dectin-2与真菌甘露聚糖以及细菌脂多糖、荚膜多糖和含有Manα1- 2 Man二糖单元的脂阿拉伯甘露聚糖结合的分子机制。
Dectin-2, a C-type lectin on macrophages and other cells of the innate immune system, functions in response to pathogens, particularly fungi. The carbohydrate-recognition domain (CRD) in dectin-2 is linked to a transmembrane sequence that interacts with the common Fc receptor γ subunit to initiate immune signaling. The molecular mechanism by which dectin-2 selectively binds to pathogens has been investigated by characterizing the CRD expressed in a bacterial system. Competition binding studies indicated that the CRD binds to monosaccharides with modest affinity and that affinity was greatly enhanced for mannose-linked α1–2 or α1–4 to a second mannose residue. Glycan array analysis confirmed selective binding of the CRD to glycans that contain Manα1–2Man epitopes. Crystals of the CRD in complex with a mammalian-type high-mannose Man9GlcNAc2 oligosaccharide exhibited interaction with Manα1–2Man on two different termini of the glycan, with the reducing-end mannose residue ligated to Ca2+ in a primary binding site and the nonreducing terminal mannose residue occupying an adjacent secondary site. Comparison of the binding sites in DC-SIGN and langerin, two other pathogen-binding receptors of the innate immune system, revealed why these two binding sites accommodate only terminal Manα1–2Man structures, whereas dectin-2 can bind Manα1–2Man in internal positions in mannans and other polysaccharides. The specificity and geometry of the dectin-2-binding site provide the molecular mechanism for binding of dectin-2 to fungal mannans and also to bacterial lipopolysaccharides, capsular polysaccharides, and lipoarabinomannans that contain the Manα1–2Man disaccharide unit.