The toll-like receptor 3:dsRNA signaling complex.
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.
Botos
Istvan
I
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Liu
Lin
L
Wang
Yan
Y
Segal
David M
DM
Davies
David R
DR
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004252:DNA Mutational Analysis; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D006031:Glycosylation; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D012330:RNA, Double-Stranded / Q000235:genetics*; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000235:genetics*
D008024:Ligands; D012330:RNA, Double-Stranded; D051196:Toll-Like Receptor 3