Molecular mechanisms for the subversion of MyD88 signaling by TcpC from virulent uropathogenic Escherichia coli
Molecular mechanisms for the subversion of MyD88 signaling by TcpC from virulent uropathogenic Escherichia coli
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DOI：
10.1073/pnas.1215770110
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发表时间：
2013-04-23
影响因子：
11.1
通讯作者：
Xiao, Tsan Sam
中科院分区：
文献类型：
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作者：
Snyder, Greg A.;Cirl, Christine;Xiao, Tsan Sam
Toll/IL-1受体（TIR）结构域是涉及Toll样受体（TLR）和IL-1受体（IL-1 R）的先天免疫应答过程中的关键信号传导模块。髓样分化因子88（MyD 88）是一个中心的含有TIR结构域的衔接子分子，负责几乎所有TLR介导的信号传导，并被来自致病性尿路致病性大肠杆菌（一种常见的人类病原体）的含有TIR结构域的蛋白C（TcpC）靶向。这种分子拮抗作用的机制仍然难以捉摸。我们提出了MyD 88 TIR结构域的晶体结构，其具有不同的环构象，强调了适配器，受体和微生物TIR结构域的功能专业化。我们的结构分析揭示了这些环以及Poc位点的基因突变。我们证明TcpC通过其预测的DD和BB环直接与MyD 88和TLR 4相关，以损害TLR诱导的细胞因子诱导。此外，NMR滴定实验确定了TcpC相互作用表面MyD 88的独特CD，DE和EE环，表明TcpC特异性地接合这些MyD 88结构元件用于免疫抑制。这些发现为尿路致病性大肠杆菌对TLR信号转导的破坏提供了分子基础。大肠杆菌毒力因子TcpC和提供一个框架的设计新的治疗药物，调节免疫激活。
The Toll/IL-1 receptor (TIR) domains are crucial signaling modules during innate immune responses involving the Toll-like receptors (TLRs) and IL-1 receptor (IL-1R). Myeloid differential factor 88 (MyD88) is a central TIR domain-containing adapter molecule responsible for nearly all TLR-mediated signaling and is targeted by a TIR domain-containing protein C (TcpC) from virulent uropathogenic Escherichia coli, a common human pathogen. The mechanism of such molecular antagonism has remained elusive. We present the crystal structure of the MyD88 TIR domain with distinct loop conformations that underscore the functional specialization of the adapter, receptor, and microbial TIR domains. Our structural analyses shed light on the genetic mutations at these loops as well as the Poc site. We demonstrate that TcpC directly associates with MyD88 and TLR4 through its predicted DD and BB loops to impair the TLR-induced cytokine induction. Furthermore, NMR titration experiments identify the unique CD, DE, and EE loops from MyD88 at the TcpC-interacting surface, suggesting that TcpC specifically engages these MyD88 structural elements for immune suppression. These findings thus provide a molecular basis for the subversion of TLR signaling by the uropathogenic E. coli virulence factor TcpC and furnish a framework for the design of novel therapeutic agents that modulate immune activation.