Structural Reorganization of the Toll-Like Receptor 8 Dimer Induced by Agonistic Ligands
Structural Reorganization of the Toll-Like Receptor 8 Dimer Induced by Agonistic Ligands
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DOI：
10.1126/science.1229159
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发表时间：
2013-03-22
期刊：
影响因子：
56.9
通讯作者：
Shimizu, Toshiyuki
中科院分区：
文献类型：
--
作者：
Tanji, Hiromi;Ohto, Umeharu;Shimizu, Toshiyuki
Toll样受体7（TLR 7）和TLR 8识别单链RNA并启动先天性免疫应答。TLR 7-TLR 8的几种合成激动剂显示出新的治疗潜力;然而，TLR 7或TLR 8识别配体和激活信号传导的分子基础在很大程度上是未知的。在这项研究中，未配体和配体诱导激活的人TLR 8二聚体的晶体结构进行了阐明。配体识别介导的二聚化界面形成的两个原聚体。在配体刺激后，TLR 8二聚体重组，使得两个C末端接近。富含亮氨酸的重复序列14（LRR 14）和LRR 15之间的环被切割;然而，N-和C-末端的一半仍然相关，并有助于配体识别和二聚化。因此，配体结合诱导TLR 8二聚体的重组，这使得下游信号传导过程成为可能。
Toll-like receptor 7 (TLR7) and TLR8 recognize single-stranded RNA and initiate innate immune responses. Several synthetic agonists of TLR7-TLR8 display novel therapeutic potential; however, the molecular basis for ligand recognition and activation of signaling by TLR7 or TLR8 is largely unknown. In this study, the crystal structures of unliganded and ligand-induced activated human TLR8 dimers were elucidated. Ligand recognition was mediated by a dimerization interface formed by two protomers. Upon ligand stimulation, the TLR8 dimer was reorganized such that the two C termini were brought into proximity. The loop between leucine-rich repeat 14 (LRR14) and LRR15 was cleaved; however, the N- and C-terminal halves remained associated and contributed to ligand recognition and dimerization. Thus, ligand binding induces reorganization of the TLR8 dimer, which enables downstream signaling processes.