Ligand-induced conformational changes allosterically activate Toll-like receptor 9
Ligand-induced conformational changes allosterically activate Toll-like receptor 9
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DOI：
10.1038/ni1479
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发表时间：
2007-07-01
影响因子：
30.5
通讯作者：
Golenbock, Douglas T.
中科院分区：
文献类型：
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作者：
Latz, Eicke;Verma, Anjali;Golenbock, Douglas T.
富含CpG二核苷酸的微生物和合成DNA可刺激Toll样受体9（TLR9），而缺乏CpG的DNA要么无活性，要么可抑制TLR9的激活。TLR9被激活或被抑制的分子机制尚不清楚。在此我们表明，TLR9可与刺激性和抑制性DNA结合；然而，只有刺激性DNA会导致TLR9胞外结构域发生显著的构象变化。在稳态下，“无活性”的TLR9同源二聚体以失活构象形成。含有CpG的DNA（而非缺乏CpG的DNA）与TLR9二聚体结合会导致TLR9胞质信号结构域发生变构变化。在内体中，含有CpG的DNA诱导的构象变化导致胞质信号结构域紧密靠近，这种变化可能是招募信号衔接分子所必需的。我们的研究结果表明，TLR9二聚体的形成不足以使其激活，相反，TLR9的激活是由含有CpG的DNA诱导的构象变化所调控的。
Microbial and synthetic DNA rich in CpG dinucleotides stimulates Toll-like receptor 9 (TLR9), whereas DNA lacking CpG either is inert or can inhibit TLR9 activation. The molecular mechanisms by which TLR9 becomes activated or is inhibited are not well understood. Here we show that TLR9 bound to stimulatory and inhibitory DNA; however, only stimulatory DNA led to substantial conformational changes in the TLR9 ectodomain. In the steady state, 'inactive' TLR9 homodimers formed in an inactivated conformation. Binding of DNA containing CpG, but not of DNA lacking CpG, to TLR9 dimers resulted in allosteric changes in the TLR9 cytoplasmic signaling domains. In endosomes, conformational changes induced by DNA containing CpG resulted in close apposition of the cytoplasmic signaling domains, a change that is probably required for the recruitment of signaling adaptor molecules. Our results indicate that the formation of TLR9 dimers is not sufficient for its activation but instead that TLR9 activation is regulated by conformational changes induced by DNA containing CpG.