Department of Pediatrics, Graduate School of Medicine, Gifu University, Yanagido 1-1, Gifu 501-1194, Japan.
Mol Immunol. 2012 Oct;52(3-4):108-16. doi: 10.1016/j.molimm.2012.05.003. Epub 2012 Jun 4.
Toll-like receptor (TLR) signaling is initiated by the binding of various adaptor proteins through ligand-induced oligomerization of the Toll/interleukin-1 receptor (TIR) domains of the TLRs. TLR2, which recognizes peptidoglycans, lipoproteins or lipopeptides derived from Gram-positive bacteria, is known to use the TIR domain-containing adaptor proteins myeloid differentiating factor 88 (MyD88) and MyD88 adaptor-like (Mal). Molecular analyses of the binding specificity of MyD88, Mal, and TLR2 are important for understanding the initial defenses mounted against Gram-positive bacterial infections such as Streptococcus pneumoniae. However, the detailed molecular mechanisms involved in the multiple interactions of these TIR domains remain unclear. Our study demonstrates that the TIR domain proteins MyD88, Mal, TLR1, and TLR2 directly bind to each other in vitro. We have also identified two binding interfaces of the MyD88 TIR domain for the TLR2 TIR domain. A residue at these interfaces has recently been found to be mutated in innate immune deficiency patients. These novel insights into the binding mode of TIR proteins will contribute to elucidation of the mechanisms underlying innate immune deficiency diseases, and to future structural studies of hetero-oligomeric TIR-TIR complexes.
Toll 样受体（TLR）信号是通过 TLR 的 Toll/白细胞介素-1 受体（TIR）结构域的配体诱导寡聚化，与各种衔接蛋白结合而启动的。TLR2 识别肽聚糖、脂蛋白或阳性细菌衍生的脂肽，已知其使用含 TIR 结构域的衔接蛋白髓样分化因子 88（MyD88）和 MyD88 衔接样蛋白（Mal）。MyD88、Mal 和 TLR2 的结合特异性的分子分析对于理解针对肺炎链球菌等阳性细菌感染的初始防御至关重要。然而，这些 TIR 结构域的多个相互作用所涉及的详细分子机制仍不清楚。我们的研究表明，TIR 结构域蛋白 MyD88、Mal、TLR1 和 TLR2 可在体外直接相互结合。我们还确定了 MyD88 TIR 结构域与 TLR2 TIR 结构域的两个结合界面。这些界面上的一个残基最近在先天免疫缺陷患者中发现发生了突变。这些关于 TIR 蛋白结合模式的新见解将有助于阐明先天免疫缺陷疾病的机制，并为未来的异源 TIR-TIR 寡聚体的结构研究提供帮助。
