Peter Mirjam E, Kubarenko Andriy V, Weber Alexander N R, Dalpke Alexander H
Department of Medical Microbiology and Hygiene, University Heidelberg, Heidelberg, Germany.
J Immunol. 2009 Jun 15;182(12):7690-7. doi: 10.4049/jimmunol.0900819.
Although it is well established that TLR9 recognizes CpG-DNA, the structural details of ligand-receptor interaction are still mostly unknown. The extracellular domain of TLR9 is composed of 25 leucine-rich repeat (LRR) motifs, 5 of which bear inserting sequences that do not conform to the LRR consensus motif. In this study, we show that the functional integrity of the extracellular domain of murine TLR9 is lost by deletion of individual LRR motifs. When deleting only the inserting sequences, we observed that LRR2, 5, and 8 contribute to receptor activation by CpG-DNA. The latter deletions did not affect receptor dimerization but inhibited CpG-DNA binding. On the basis of a homology modeling approach, we furthermore identify a positively charged region in the N terminus that is essential for CpG-DNA-induced TLR9 activation. This interaction site mirrors findings previously shown for the structural recognition of dsRNA by TLR3 and hints toward a general principle of nucleic acid recognition by the respective TLR.
尽管Toll样受体9（TLR9）识别CpG-DNA这一点已得到充分证实，但配体-受体相互作用的结构细节大多仍不清楚。TLR9的胞外域由25个富含亮氨酸的重复序列（LRR）基序组成，其中5个带有不符合LRR共有基序的插入序列。在本研究中，我们表明，通过缺失单个LRR基序，小鼠TLR9胞外域的功能完整性丧失。当仅缺失插入序列时，我们观察到LRR2、5和8有助于CpG-DNA激活受体。后一种缺失不影响受体二聚化，但抑制CpG-DNA结合。基于同源建模方法，我们进一步在N端鉴定出一个带正电荷的区域，该区域对于CpG-DNA诱导的TLR9激活至关重要。该相互作用位点反映了先前TLR3对双链RNA结构识别的研究结果，并暗示了相应TLR识别核酸的一般原理。
