The toll-like receptor 3:dsRNA signaling complex

Biochim Biophys Acta. Sep-Oct 2009;1789(9-10):667-74. doi: 10.1016/j.bbagrm.2009.06.005. Epub 2009 Jul 9.

Abstract

Toll-like receptors (TLRs) recognize conserved molecular patterns in invading pathogens and trigger innate immune responses. TLR3 recognizes dsRNA, a molecular signature of most viruses via its ectodomain (ECD). The TLR3-ECD structure consists of a 23 turn coil bent into the shape of a horseshoe with specialized domains capping the N and C-terminal ends of the coil. TLR3-ECDs bind as dimeric units to dsRNA oligonucleotides of at least 45 bp in length, the minimal length required for signal transduction. X-ray analysis has shown that each TLR3-ECD of a dimer binds dsRNA at two sites located at opposite ends of the TLR3 "horseshoe" on the one lateral face that lacks N-linked glycans. Intermolecular contacts between the C-terminal domains of two TLR3-ECDs stabilize the dimer and position the C-terminal residues within 20-25 A of each other, which is thought to be essential for transducing a signal across the plasma membrane in intact TLR3 molecules. Interestingly, in TLRs 1, 2 and 4, which bind lipid ligands using very different interactions from TLR3, the ligands nevertheless promote the formation of a dimer in which the same two lateral surfaces as in the TLR3-ECD:dsRNA complex face each other, bringing their C-termini in close proximity. Thus, a pattern is emerging in which pathogen-derived substances bind to TLR-ECDs, thereby promoting the formation of a dimer in which the glycan-free ligand binding surfaces face each other and the two C-termini are brought in close proximity for signal transduction.

Publication types

  • Review

MeSH terms

  • Animals
  • Cell Membrane / metabolism
  • DNA Mutational Analysis
  • Dimerization
  • Dose-Response Relationship, Drug
  • Glycosylation
  • Humans
  • Kinetics
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Polymorphism, Single Nucleotide
  • Protein Structure, Tertiary
  • RNA, Double-Stranded / genetics*
  • Signal Transduction
  • Toll-Like Receptor 3 / genetics*

Substances

  • Ligands
  • RNA, Double-Stranded
  • Toll-Like Receptor 3