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Structural basis for signal transduction by the Toll/interleukin-1 receptor domains

机译：Toll /白介素-1受体域信号转导的结构基础

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摘要

Toll-like receptors (TLRs) and the interleukin-1 receptor super-family (IL-1Rs) are integral to both innate and adaptive immunity for host defence. These receptors share a conserved cytoplasmic domain, known as the TIR domain. A single-point mutation in the TIR domain of murine TLR4 (Pro712His, the Lps~d mutation) abolishes the host immune response to lipopolysaccharide (LPS), and mutation of the equivalent residue in TLR2, Pro681His, disrupts signal transduction in response to stimulation by yeast and Gram-positive bacteria. Here we report the crystal structures of the TIR domains of human TLR1 and TLR2 and of the Pro681His mutant of TLR2. The structures have a large conserved surface patch that also contains the site of the Lps~d mutation. Mutagenesis and functional studies confirm that residues in this surface patch are crucial for receptor signalling. The Lps~d mutation does not disturb the structure of the TIR domain itself. Instead, structural and functional studies indicate that the conserved surface patch may mediate interactions with the downstream MyD88 adapter molecule, and that the Lps~d mutation may abolish receptor signalling by disrupting this recruitment.
机译：Toll样受体（TLR）和白介素1受体超家族（IL-1R）对宿主防御的先天免疫和适应性免疫都是不可或缺的。这些受体共享保守的胞质结构域，称为TIR结构域。鼠TLR4的TIR域中的单点突变（Pro712His，Lps〜d突变）消除了宿主对脂多糖（LPS）的免疫反应，而TLR2中的等效残基Pro681His的突变破坏了对刺激的信号传导由酵母菌和革兰氏阳性菌引起。在这里，我们报告人类TLR1和TLR2的TIR域和TLR2的Pro681His突变体的晶体结构。这些结构具有较大的保守表面斑块，其中也包含Lps_d突变的位点。诱变和功能研究证实，该表面补丁中的残基对于受体信号传导至关重要。 Lps_d突变不会干扰TIR结构域本身的结构。相反，结构和功能研究表明，保守的表面补丁可能介导与下游MyD88衔接子分子的相互作用，而Lps_d突变可能会通过破坏这种募集而废除受体信号传导。

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