Binding Sites for Acylated Trehalose Analogs of Glycolipid Ligands on an Extended Carbohydrate Recognition Domain of the Macrophage Receptor Mincle.
Binding Sites for Acylated Trehalose Analogs of Glycolipid Ligands on an Extended Carbohydrate Recognition Domain of the Macrophage Receptor Mincle.
复制标题
在巨噬细胞受体Mincle的扩展碳水化合物识别结构域上的糖脂配体酰化的沙洛糖类似物的结合位点。
DOI：
10.1074/jbc.m116.749515
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发表时间：
2016-09-30
期刊：
影响因子：
--
通讯作者：
Drickamer K
中科院分区：
文献类型：
--
作者：
Feinberg H;Rambaruth ND;Jégouzo SA;Jacobsen KM;Djurhuus R;Poulsen TB;Weis WI;Taylor ME;Drickamer K
巨噬细胞受体与结核分枝杆菌表面的海藻糖二霉菌酸酯结合。由这种相互作用引发的信号传导导致细胞因子的产生，这是分枝杆菌逃避免疫系统的能力的基础，也可以作为佐剂发挥作用。在以前的工作中，海藻糖二霉菌酸酯的糖头基与切碎物结合的机制已经阐明，但增强与糖脂配体结合的基础，其中疏水取代基连接到6-羟基基团，一直是推测的主题。在这里报告的工作中，海藻糖衍生物与牛碎肉的相互作用已被探测与一系列的海藻糖二霉菌酸酯的合成模拟物在结合试验中，在结构研究中，通过X射线晶体学，并通过定点诱变。结合研究表明，而不是反映特定的结构偏好，与疏水取代基的配体的mincle的表观亲和力与它们的整体大小相关。结构和诱变分析提供了证据的疏水性取代基与多个不同部分的表面的碎肉的相互作用，并确认存在三个Ca 2+结合位点。在最小C型碳水化合物识别结构域之外，mincle细胞外结构域的延伸部分的结构也限制了结合结构域在巨噬细胞表面上相互作用的方式。
The macrophage receptor mincle binds to trehalose dimycolate on the surface of Mycobacterium tuberculosis. Signaling initiated by this interaction leads to cytokine production, which underlies the ability of mycobacteria to evade the immune system and also to function as adjuvants. In previous work the mechanism for binding of the sugar headgroup of trehalose dimycolate to mincle has been elucidated, but the basis for enhanced binding to glycolipid ligands, in which hydrophobic substituents are attached to the 6-hydroxyl groups, has been the subject of speculation. In the work reported here, the interaction of trehalose derivatives with bovine mincle has been probed with a series of synthetic mimics of trehalose dimycolate in binding assays, in structural studies by x-ray crystallography, and by site-directed mutagenesis. Binding studies reveal that, rather than reflecting specific structural preference, the apparent affinity of mincle for ligands with hydrophobic substituents correlates with their overall size. Structural and mutagenesis analysis provides evidence for interaction of the hydrophobic substituents with multiple different portions of the surface of mincle and confirms the presence of three Ca2+-binding sites. The structure of an extended portion of the extracellular domain of mincle, beyond the minimal C-type carbohydrate recognition domain, also constrains the way the binding domains may interact on the surface of macrophages.