Soluble human TLR2 ectodomain binds diacylglycerol from microbial lipopeptides and glycolipids.
Soluble human TLR2 ectodomain binds diacylglycerol from microbial lipopeptides and glycolipids.
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DOI：
10.1177/1753425914524077
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发表时间：
2015-02
期刊：
影响因子：
3.2
通讯作者：
Wilson IA
中科院分区：
文献类型：
--
作者：
Jiménez-Dalmaroni MJ;Radcliffe CM;Harvey DJ;Wormald MR;Verdino P;Ainge GD;Larsen DS;Painter GF;Ulevitch R;Beutler B;Rudd PM;Dwek RA;Wilson IA
toll样受体（TLRs）是识别微生物中生物分子保守特征的关键先天免疫受体。特别是，已有报道称TLR2可被不同种类的微生物配体激活。为了进一步了解TLR2与配体的相互作用，利用杆状病毒/昆虫细胞表达系统表达了重组人TLR2外结构域（hTLR2ED），并研究了其生化特性和配体结合特性。hTLR2ED在缺乏共受体TLR1和TLR6的细胞外生理条件下结合合成细菌和支原体脂肽、来自金黄色葡萄球菌的脂质胆酸（LTA）和来自分枝杆菌的合成脂arabinom聚糖前体。我们还确定脂肽和糖脂不能同时与hTLR2ED结合，磷脂酰肌醇甘露苷2 （Pim2）是与hTLR2ED结合的最小脂阿拉伯甘露聚糖结构。hTLR2ED与含有二酰基甘油基团的Pim4结合，表明hTLR2ED可以与酰基链长度超过16个碳原子的配体结合。综上所述，我们的数据表明，二酰基甘油是微生物糖脂和脂蛋白结合hTLR2ED的配体部分，两种类型的配体结合hTLR2ED的相同结合位点。新型TLR2抑制剂的设计，基于其与TLR2结合而不激活TLR2信号通路的能力，可能会导致革兰氏阳性菌引起的脓毒性休克的新治疗方法的发展。
Toll-like receptors (TLRs) are key innate immune receptors that recognize conserved features of biological molecules that are found in microbes. In particular, TLR2 has been reported to be activated by different kinds of microbial ligands. To advance our understanding of the interaction of TLR2 with its ligands, the recombinant human TLR2 ectodomain (hTLR2ED) was expressed using a baculovirus/insect cell expression system, and its biochemical as well as ligand binding properties were investigated. The hTLR2ED binds synthetic bacterial and mycoplasmal lipopeptides, lipoteichoic acid (LTA) from Staphylococcus aureus, and synthetic lipoarabinomannan precursors from Mycobacterium at extracellular physiological conditions, in the absence of its co-receptors TLR1 and TLR6. We also determined that lipopeptides and glycolipids cannot bind simultaneously to hTLR2ED and that the phosphatidyl inositol mannoside 2 (Pim2) is the minimal lipoarabinomannan structure for binding to hTLR2ED. Binding of hTLR2ED to Pim4, which contains a diacylglycerol group with one of its acyl chain containing 19 carbon atoms, indicates that hTLR2ED can bind ligands with acyl chains longer than 16 carbon atoms. In summary, our data indicate that diacylglycerol is the ligand moiety of microbial glycolipids and lipoproteins that bind to hTLR2ED and that both types of ligands bind to the same binding site of hTLR2ED. The design of novel inhibitors of TLR2, based on their ability to bind to TLR2 but not activate the TLR2 signaling pathway, may lead to the development of novel treatments for septic shock caused by Gram- positive bacteria.
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影响因子：
64.8
作者：
Hoebe, K;Georgel, P;Beutler, B
通讯作者：
Beutler, B
影响因子：
3.5
作者：
Ainge, Gary D.;Hudson, Jennifer;Harper, Jacquie L.
通讯作者：
Harper, Jacquie L.
影响因子：
4.4
作者：
Irvine KL;Hopkins LJ;Gangloff M;Bryant CE
通讯作者：
Bryant CE
影响因子：
--
作者：
Deininger, Susanne;Figueroa-Perez, Ignacio;von Aulock, Sonja
通讯作者：
von Aulock, Sonja
DOI：
10.1073/pnas.0505077102
发表时间：
2005-08-02
影响因子：
11.1
作者：
Bell, JK;Botos, I;Davies, DR
通讯作者：
Davies, DR