Ve Thomas, Vajjhala Parimala R, Hedger Andrew, Croll Tristan, DiMaio Frank, Horsefield Shane, Yu Xiong, Lavrencic Peter, Hassan Zahid, Morgan Garry P, Mansell Ashley, Mobli Mehdi, O'Carroll Ailis, Chauvin Brieuc, Gambin Yann, Sierecki Emma, Landsberg Michael J, Stacey Katryn J, Egelman Edward H, Kobe Bostjan
School of Chemistry and Molecular Biosciences, and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland, Australia.
Institute for Glycomics, Griffith University, Southport, Queensland, Australia.
Nat Struct Mol Biol. 2017 Sep;24(9):743-751. doi: 10.1038/nsmb.3444. Epub 2017 Jul 31.
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.
Toll样受体（TLR）信号传导是对病原体的关键先天性免疫反应。诸如MAL（TIRAP）和MyD88等信号衔接蛋白向TLR的募集需要Toll/白细胞介素-1受体（TIR）结构域相互作用，但其结构仍不清楚。在这里，我们表明MAL TIR结构域在体外能自发且可逆地形成细丝。它们还能与TLR4 TIR结构域形成共细丝，并诱导MyD88组装体的形成。一个7埃分辨率的冷冻电镜结构揭示了一种稳定的MAL原丝，由两条平行的TIR结构域亚基链以BB环介导的头对头排列组成。对相互作用重要的界面残基在不同的TIR结构域中是保守的。尽管在细胞信号传导过程中不太可能形成TLR4、MAL或MyD88的大细丝，但结构导向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TLR和白细胞介素-1受体信号传导中涉及的TIR结构域相互作用保守模式的模板。
