Recognition of Lipopeptide Patterns by Toll-like Receptor 2-Toll-like Receptor 6 Heterodimer
Recognition of Lipopeptide Patterns by Toll-like Receptor 2-Toll-like Receptor 6 Heterodimer
复制标题
DOI：
10.1016/j.immuni.2009.09.018
复制
发表时间：
2009-12-18
期刊：
影响因子：
32.4
通讯作者：
Lee, Jie-Oh
中科院分区：
文献类型：
--
作者：
Kang, Jin Young;Nan, Xuehua;Lee, Jie-Oh
Toll 样受体 2 (TLR2) 通过识别二酰化和三酰化脂肽来启动有效的免疫反应。其配体特异性由其是否与 TLR1 或 TLR6 异二聚化来控制。我们已经确定了TLR2-TLR6-二酰化脂肽、TLR2-脂磷壁酸和TLR2-PE-DTPA复合物的晶体结构。 PE-DTPA，1,2-二肉豆蔻酰基-sn-甘油-3-磷酸乙醇胺-N-二乙三胺五乙酸，是一种合成磷脂衍生物。 TLR2-TLR1 或 TLR2-TLR6 异二聚体的配体特异性有两个主要因素。首先，TLR6 的脂质通道被两个苯丙氨酸阻断。这些苯丙氨酸的同时突变使得TLR2-TLR6不仅对二酰化脂肽而且对三酰化脂肽完全响应。其次，TLR2-TLR6的疏水二聚化界面增加了80%，这补偿了脂肽与TLR2-TLR6之间酰胺脂质相互作用的缺乏。 TLR2-脂磷壁酸和TLR2-PE-DTPA复合物的结构表明，头基的精确相互作用模式对于TLR2异二聚体的强大免疫反应至关重要。
Toll-like receptor 2 (TLR2) initiates potent immune responses by recognizing diacylated and triacylated lipopeptides. Its ligand specificity is controlled by whether it heterodimerizes with TLR1 or TLR6. We have determined the crystal structures of TLR2-TLR6-diacylated lipopeptide, TLR2-lipoteichoic acid, and TLR2-PE-DTPA complexes. PE-DTPA, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-diethy-lenetriaminepentaacetic acid, is a synthetic phospholipid derivative. Two major factors contribute to the ligand specificity of TLR2-TLR1 or TLR2-TLR6 heterodimers. First, the lipid channel of TLR6 is blocked by two phenylalanines. Simultaneous mutation of these phenylalanines made TLR2-TLR6 fully responsive not only to diacylated but also to triacylated lipopeptides. Second, the hydrophobic dimerization interface of TLR2-TLR6 is increased by 80%, which compensates for the lack of amide lipid interaction between the lipopeptide and TLR2-TLR6. The structures of the TLR2-lipoteichoic acid and the TLR2-PE-DTPA complexes demonstrate that a precise interaction pattern of the head group is essential for a robust immune response by TLR2 heterodimers.