Autoinhibition and relief mechanism by the proteolytic processing of Toll-like receptor 8

作者：Tanji Hiromi; Ohto Umeharu; Motoi Yuji; Shibata Takuma; Miyake Kensuke; Shimizu Toshiyuki^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(11): 3012-3017.

DOI：10.1073/pnas.1516000113

• Toll-like receptor
• innate immunity
• proteolytic processing
• X-ray crystallography
• Z-loop

Toll-like receptor 8 (TLR8) senses single-stranded RNA (ssRNA) and initiates innate immune responses. TLR8 requires proteolytic cleavage at the loop region (Z-loop) between leucine-rich repeat (LRR) 14 and LRR15 for its activation. However, the molecular basis of Z-loop processing remains unknown. To elucidate the mechanism of Z-loop processing, we performed biochemical and structural studies of how the Z-loop affects the function of TLR8. TLR8 with the uncleaved Z-loop is unable to form a dimer, which is essential for activation, irrespective of the presence of agonistic ligands. Crystallographic analysis revealed that the uncleaved Z-loop located on the ascending lateral face prevents the approach of the dimerization partner by steric hindrance. This autoinhibition mechanism of dimerization by the Z-loop might be occurring in the proteins of the same subfamily, TLR7 and TLR9.

• 出版日期2016-3-15