Botos Istvan, Liu Lin, Wang Yan, Segal David M, Davies David R
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Biochim Biophys Acta. 2009 Sep-Oct;1789(9-10):667-74. doi: 10.1016/j.bbagrm.2009.06.005. Epub 2009 Jul 9.
Toll-like receptors (TLRs) recognize conserved molecular patterns in invading pathogens and trigger innate immune responses. TLR3 recognizes dsRNA, a molecular signature of most viruses via its ectodomain (ECD). The TLR3-ECD structure consists of a 23 turn coil bent into the shape of a horseshoe with specialized domains capping the N and C-terminal ends of the coil. TLR3-ECDs bind as dimeric units to dsRNA oligonucleotides of at least 45 bp in length, the minimal length required for signal transduction. X-ray analysis has shown that each TLR3-ECD of a dimer binds dsRNA at two sites located at opposite ends of the TLR3 "horseshoe" on the one lateral face that lacks N-linked glycans. Intermolecular contacts between the C-terminal domains of two TLR3-ECDs stabilize the dimer and position the C-terminal residues within 20-25 A of each other, which is thought to be essential for transducing a signal across the plasma membrane in intact TLR3 molecules. Interestingly, in TLRs 1, 2 and 4, which bind lipid ligands using very different interactions from TLR3, the ligands nevertheless promote the formation of a dimer in which the same two lateral surfaces as in the TLR3-ECD:dsRNA complex face each other, bringing their C-termini in close proximity. Thus, a pattern is emerging in which pathogen-derived substances bind to TLR-ECDs, thereby promoting the formation of a dimer in which the glycan-free ligand binding surfaces face each other and the two C-termini are brought in close proximity for signal transduction.
Toll样受体（TLR）识别入侵病原体中的保守分子模式并触发先天性免疫反应。TLR3通过其胞外域（ECD）识别双链RNA（dsRNA），这是大多数病毒的分子标志。TLR3-ECD结构由一个23圈的螺旋组成，弯曲成马蹄形，在螺旋的N端和C端有特殊结构域。TLR3-ECD以二聚体形式与长度至少为45bp的dsRNA寡核苷酸结合，这是信号转导所需的最小长度。X射线分析表明，二聚体中每个TLR3-ECD在TLR3“马蹄形”一侧面缺乏N-连接聚糖的相对两端的两个位点结合dsRNA。两个TLR3-ECD的C端结构域之间的分子间接触稳定了二聚体，并使C端残基彼此相距20-25埃，这被认为对于完整TLR3分子跨质膜转导信号至关重要。有趣的是，在使用与TLR3非常不同的相互作用结合脂质配体的TLR1、2和4中，配体仍然促进形成二聚体，其中与TLR3-ECD:dsRNA复合物中相同的两个侧面彼此相对，使它们的C端靠近。因此，一种模式正在显现，即病原体衍生物质与TLR-ECD结合，从而促进形成一种二聚体，其中无糖基的配体结合表面彼此相对，并且两个C端靠近以进行信号转导。
