Toll-like receptor (TLR) signaling is a key innate immunity response to pathogens. Recruitment of signaling adapters such as MAL (TIRAP) and MyD88 to the TLRs requires Toll/interleukin-1 receptor (TIR)-domain interactions, which remain structurally elusive. Here we show that MAL TIR domains spontaneously and reversibly form filaments in vitro. They also form cofilaments with TLR4 TIR domains and induce formation of MyD88 assemblies. A 7-Å-resolution cryo-EM structure reveals a stable MAL protofilament consisting of two parallel strands of TIR-domain subunits in a BB-loop-mediated head-to-tail arrangement. Interface residues that are important for the interaction are conserved among different TIR domains. Although large filaments of TLR4, MAL or MyD88 are unlikely to form during cellular signaling, structure-guided mutagenesis, combined with in vivo interaction assays, demonstrated that the MAL interactions defined within the filament represent a template for a conserved mode of TIR-domain interaction involved in both TLR and interleukin-1 receptor signaling.

中文翻译：

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依赖MAL和MyD88的TLR4信号传导中TIR域组装形成的结构基础

Toll样受体（TLR）信号是对病原体的关键先天免疫应答。向TLR招募诸如MAL（TIRAP）和MyD88之类的信号转接头需要Toll / interleukin-1受体（TIR）域相互作用，但在结构上仍然难以捉摸。在这里，我们显示MAL TIR域在体外自发且可逆地形成细丝。它们还与TLR4 TIR结构域形成共丝并诱导MyD88装配体的形成。分辨率为7-Å的cryo-EM结构揭示了稳定的MAL原丝，该原丝由BB环介导的头到尾排列的TIR域亚基的两条平行链组成。对于相互作用重要的界面残基在不同的TIR结构域之间是保守的。尽管TLR4，MAL或MyD88的大细丝不太可能在细胞信号传导过程中形成，但结构指导的诱变结合体内相互作用测定表明，细丝内定义的MAL相互作用代表了TIR域相互作用保守模式的模板参与TLR和白介素1受体信号转导。