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

Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):3012-7. doi: 10.1073/pnas.1516000113. Epub 2016 Feb 29.

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.

Keywords: Toll-like receptor; X-ray crystallography; Z-loop; innate immunity; proteolytic processing.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Crystallography, X-Ray
  • Dimerization
  • Genes, Reporter
  • HEK293 Cells
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • NF-kappa B / metabolism
  • Peptide Hydrolases / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Processing, Post-Translational*
  • Protein Structure, Tertiary
  • Proteolysis
  • Recombinant Fusion Proteins / metabolism
  • Sequence Alignment
  • Toll-Like Receptor 8 / chemistry
  • Toll-Like Receptor 8 / genetics
  • Toll-Like Receptor 8 / metabolism*

Substances

  • Ligands
  • NF-kappa B
  • Recombinant Fusion Proteins
  • TLR8 protein, human
  • Toll-Like Receptor 8
  • Peptide Hydrolases

Associated data

  • PDB/5HDH