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Structural biology of Toll like receptor/IL 1R signaling

Toll 样受体/IL 1R 信号传导的结构生物学

基本信息

批准号：
6870169
负责人：
LIANG TONG
金额：
$ 29.84万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-03-01 至 2007-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6870169
关键词：
X ray crystallography biological signal transduction cell line cytokine receptors gene mutation interleukin 1 protein structure function recombinant proteins site directed mutagenesis stoichiometry

项目摘要

Toll-like receptors (TLRs) and members of the interleukin-1 receptor (IL-lR) superfamily have crucial roles in host innate immune response against microbial infections. For example, deletion of the TLR4 gene in mice renders them hyporesponsive to lipopolysaccharide (LPS, also known as endotoxin), which is a unique cell-wall component of Gram-negative bacteria. In mammals and other vertebrates, the innate immune response is also important for the activation of the proper adaptive immune response. The TLRs and the IL-1RS share a conserved intra-cellular domain, the Toll/Interleukin-1 Receptor (TIR) domain. The integrity of this domain is required for the signal transduction through these receptors. For example, a single-point mutation in the TIR domain of murine TLR4, P712H, leads to the abrogation of LPS responsiveness, similar to the phenotype of the TLR4-/- mice. Additional mutagenesis studies also confirm the importance of this domain in the signaling process. The signaling pathway of the TLRs and IL-1RS involves many molecules, such as the adapter molecule MyD88, the protein kinase IRAK, TRAF6, and other down-stream mediators. MyD88 is a cytoplasmic protein and it also contains a TIR domain. Ultimately, the signal transduction leads to the activation of the transcription factor NF-kappaB, the stress kinases and the AP-1 transcription factors. TIR domains are believed to be protein-protein interaction modules. Upon receptor activation by ligand binding, an intra-cellular signaling complex is formed via the TIR domains that are present in the receptors and the MyD88 adapter molecule. This is a crucial step in the signal transduction by these receptors. Currently, there is no structural information on any of the TIR domains. The proposed research project will fill this gap in our knowledge on these signal transduction modules. The structural information will be used to understand the biology and biochemistry of the TLRs and the IL-1RS. The information will also be used to identify residues that may be important for the signal transduction. These will form the basis for further mutagenesis, biochemical, and functional studies to assess their importance.

Toll样受体(TLRs)和白介素1受体(IL-LR)超家族成员在宿主抵抗微生物感染的先天免疫反应中发挥重要作用。例如，小鼠体内TLR4基因的缺失使它们对内毒素(LPS，也称为内毒素)反应迟钝，内毒素是革兰氏阴性细菌的一种独特的细胞壁成分。在哺乳动物和其他脊椎动物中，先天免疫反应对于激活适当的适应性免疫反应也是重要的。TLRs和IL-1Rs共享一个保守的细胞内结构域，即Toll/IL-1受体(TIR)结构域。这个结构域的完整性是通过这些受体进行信号转导所必需的。例如，小鼠TLR4，P712H的TIR结构域的单点突变导致内毒素反应性的丧失，类似于TLR4-/-小鼠的表型。更多的突变研究也证实了该结构域在信号传递过程中的重要性。TLRs和IL-1RS的信号通路涉及许多分子，如接头分子MyD88、蛋白激酶IRAK、TRAF6等下游介体。MyD88是一种细胞质蛋白，也含有TIR结构域。最终，信号转导导致转录因子NF-kappaB、应激蛋白激酶和AP-1转录因子的激活。TIR结构域被认为是蛋白质-蛋白质相互作用模块。当受体被配体结合激活时，通过存在于受体和MyD88接头分子中的TIR结构域形成细胞内信号复合体。这是这些受体信号转导过程中至关重要的一步。目前，没有关于任何TIR结构域的结构信息。拟议的研究项目将填补我们在这些信号转导模块方面的知识空白。这些结构信息将被用来理解TLRs和IL-1Rs的生物学和生化。这些信息还将被用来识别可能对信号转导重要的残基。这些将形成进一步的突变、生化和功能研究的基础，以评估它们的重要性。