Molecular analysis of the binding mode of Toll/interleukin-1 receptor (TIR) domain proteins during TLR2 signaling.
Molecular analysis of the binding mode of Toll/interleukin-1 receptor (TIR) domain proteins during TLR2 signaling.
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TLR2 信号传导过程中 Toll/白细胞介素 1 受体 (TIR) 结构域蛋白结合模式的分子分析。
DOI：
10.1016/j.molimm.2012.05.003
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Kondo N.
中科院分区：
文献类型：
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作者：
Nada M;Ohnishi H;Tochio H;Kato Z;Kimura T;Kubota K;Yamamoto T;Kamatari YO;Tsutsumi N;Shirakawa M;Kondo N.
Toll样受体(Toll-like Receptor，TLR)信号转导通路是通过配体诱导的Toll/IL-1受体(TIR)结构域的寡聚化与多种接头蛋白结合而启动的。TLR2识别来自革兰氏阳性细菌的肽聚糖、脂蛋白或脂肽，已知使用含有TIR结构域的接头蛋白髓系分化因子88(MyD88)和类MyD88接头(MAL)。对MyD88、MAL和TLR2结合特异性的分子分析对于理解对革兰氏阳性细菌感染(如肺炎链球菌)的初始防御非常重要。然而，这些TIR结构域的多重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在体外直接相互结合。我们还鉴定了MyD88 TIR结构域与TLR2 TIR结构域的两个结合接口。最近发现，在先天性免疫缺陷患者中，这些界面上的一个残留物发生了突变。这些对TIR蛋白结合模式的新见解将有助于阐明先天性免疫缺乏性疾病的发病机制，并有助于未来对TIR-TIR异寡聚体的结构研究。
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.