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

Hiromi Tanji, Umeharu Ohto, Yuji Motoi, Takuma Shibata, Kensuke Miyake, Toshiyuki Shimizu

Journal: Proceedings of the National Academy of Sciences of the United States of America 2016;113(11):3012-7

PMID: 26929371

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Abstract

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.

Address: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan;; Division of Innate Immunity, Department of Microbiology and Immunology, Laboratory of Innate Immunity, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.; Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan; [email protected].

DOI: 10.1073/pnas.1516000113