The dsRNA binding site of human toll-like receptor 3
The dsRNA binding site of human toll-like receptor 3
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DOI：
10.1073/pnas.0603245103
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发表时间：
2006-06-06
影响因子：
11.1
通讯作者：
Segal, David M.
中科院分区：
文献类型：
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作者：
Bell, Jessica K.;Askins, Janine;Segal, David M.
Toll样受体（TLR）识别病原体启动先天免疫应答，这对于抑制病原体传播和获得性免疫的发展至关重要。TLR通过其N-末端胞外域（ECD）识别病原体，但这种识别的分子基础尚不清楚。最近，我们报道了未配体的TLR 3-ECD的X射线结构;然而，已经证明难以获得TLR 3与其配体dsRNA的晶体结构。我们现在已经通过突变分析定位了TLR 3配体结合位点。在整个TLR 3-ECD中已经产生了超过50个单残基突变，但只有两个，H539 E和N541 A，导致TLR 3活化和配体结合功能的丧失。这些突变将dsRNA结合位点定位在TLR 3的无聚糖侧表面上朝向C末端，并提出了dsRNA结合和TLR 3活化的模型。
Pathogen recognition by Toll-like receptors (TLRs) initiates innate immune responses that are essential for inhibiting pathogen dissemination and for the development of acquired immunity. The TLRs recognize pathogens with their N-terminal ectodomains (ECD), but the molecular basis for this recognition is not known. Recently we reported the x-ray structure for unliganded TLR3-ECD; however, it has proven difficult to obtain a crystal structure of TLR3 with its ligand, dsRNA. We have now located the TLR3 ligand binding site by mutational analysis. More than 50 single-residue mutations have been generated throughout the TLR3-ECD, but only two, H539E and N541A, resulted in the loss of TLR3 activation and ligand binding functions. These mutations locate the dsRNA binding site on the glycan-free, lateral surface of TLR3 toward the C terminus and suggest a model for dsRNA binding and TLR3 activation.