Structural basis of CpG and inhibitory DNA recognition by Toll-like receptor 9

Ohto, U., et al. Nature 520, 702-705 (2015)

Speaker: Jyun-Cyuan Chang (張鈞筌)             Time: 13:00~14:00, May 27, 2015

Commentator: Dr. Wen-Yih Jeng (鄭文義 老師)    Place: Room 601

Abstract:

Innate immunity plays an important role in defense invading pathogens such as bacteria and viruses. Toll-like receptors (TLRs) sense specific molecular patterns from pathogens using leucine-rich repeats (LRR). TLR9 recognizes bacterial and viral DNA containing the cysteine-phosphate-guanine (CpG) dideoxynucleotide motif (1). The molecular basis between CpG-DNA and TLR9 is still unclear. To resolve the molecular mechanisms between of DNA-bound TLR9. The authors showed three crystal structure forms of TLR9: unligand, agonistic CpG-DNA-bound, and antagonistic inhibitory DNA-bound (iDNA-bound). The crystal structure indicates that the CpG-DNA-bound TLR9 is a symmetric dimer and iDNA-bond TLR9 is a monomer (2). The authors further showed that CpG-DNA was recognized by the N-terminal LRRT-LRR10 (interface 1) and the C-terminal LRR20-LRR22 (interface2) in the dimeric form of TLR9. In the interface1 of CpG-DNA complex, GACGTT is mainly recognized by TLR9 and the C6 in CpG motif forms direct hydrogen bonding to TLR9. In contrast to interface 1, residues of interface2 engage in four hydrogen bonds and several Vander Waals interactions. Futher, the interface1 and 2 are both important for NF-ĸB activation. On the other hand, the iDNA formed a stem-loop structure and bound to LRR2-LRR10. The stem-loop is formed by base pairing between C1-C2-T3 and T7-G8-G9 in iDNA complex. Moreover, the G10 in iDNA was directly recognized by TLR9 by forming hydrogen bonds. These structures reveal the mechanism of recognition of CpG-DNA and iDNA by TLR9. Many pathogens cause sepsis and inflammatory reactions thorough the binding of CpG to TLR9. These results will improve to development of therapeutic agent for TLR9.

References:

1.    Tanji, H., Ohto, U., Shibata, T., Miyake, K. & Shimizu, T. Structural reorganization of the Toll-like receptor 8 dimer induced by agonistic ligands. Science 339, 1426-1429 (2013).

2.    Onji, M., et al. An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing. Nature communications 4, 1949 (2013).