Molecular Mimicry in Innate Immunity CRYSTAL STRUCTURE OF A BACTERIAL TIR DOMAIN
Molecular Mimicry in Innate Immunity CRYSTAL STRUCTURE OF A BACTERIAL TIR DOMAIN
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DOI：
10.1074/jbc.c109.007591
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发表时间：
2009-08-07
影响因子：
4.8
通讯作者：
Pascual, Jaime
中科院分区：
文献类型：
--
作者：
Chan, Siew Leong;Low, Lieh Yoon;Pascual, Jaime
巨噬细胞通过激活其质膜结合的 Toll 样受体蛋白 (TLR) 来检测病原体感染。 TLR 的 Toll/白细胞介素 1 受体 (TIR) 结构域与接头蛋白（如骨髓分化初级反应基因 88 (MyD88)）之间的异型相互作用是哺乳动物先天免疫反应信号传导途径中的第一个细胞内步骤。受体和衔接子的 TIR 的异源寡聚化会激活转录因子 NF-κ B，从而调节促炎细胞因子的合成。在这里，我们报告了第一个以 2.5 埃分辨率解析的细菌 TIR 结构域的晶体结构。脱氮副球菌 TIR 的三维折叠与人类 TLR 和 MyD88 蛋白的 TIR 观察到的相同。该结构显示出涉及 DD 环和 EE 环残基的独特二聚化界面，同时使 BB 环高度暴露。肽酰胺氢-氘交换质谱还表明，同一区域用于溶液中和全长蛋白质的二聚化。这些结果，加上在免疫共沉淀测定中观察到的反硝化假单胞菌 TIR 和 MyD88 之间的功能相互作用，进一步证实了细菌 TIR 蛋白采用宿主活性受体 TIR 结构域的结构模拟来干扰 TLR 及其接头的信号传导以减少炎症反应的模型。
Macrophages detect pathogen infection via the activation of their plasma membrane-bound Toll-like receptor proteins (TLRs). The heterotypic interaction between the Toll/interleukin-1 receptor (TIR) domains of TLRs and adaptor proteins, like Myeloid differentiation primary response gene 88 (MyD88), is the first intracellular step in the signaling pathway of the mammalian innate immune response. The hetero-oligomerization of the TIRs of the receptor and adaptor brings about the activation of the transcription factor NF-kappa B, which regulates the synthesis of pro-inflammatory cytokines. Here, we report the first crystal structure of a bacterial TIR domain solved at 2.5 angstrom resolution. The three-dimensional fold of Paracoccus denitrificans TIR is identical to that observed for the TIR of human TLRs and MyD88 proteins. The structure shows a unique dimerization interface involving the DD-loop and EE-loop residues, whereas leaving the BB-loop highly exposed. Peptide amide hydrogen-deuterium exchange mass spectrometry also reveals that the same region is used for dimerization in solution and in the context of the full-length protein. These results, together with a functional interaction between P. denitrificans TIR and MyD88 visualized in a co-immunoprecipitation assay, further substantiate the model that bacterial TIR proteins adopt structural mimicry of the host active receptor TIR domains to interfere with the signaling of TLRs and their adaptors to decrease the inflammatory response.