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Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling
Published on: July 26, 2017
The toll-like receptor 3:dsRNA signaling complex
Istvan Botos1, Lin Liu, Yan Wang
1Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Biochimica Et Biophysica Acta
|July 15, 2009
Summary
Toll-like receptors (TLRs) dimerize upon binding pathogen molecules like dsRNA or lipids. This dimerization, mediated by specific ectodomain surfaces, brings C-terminal domains together, initiating innate immune signaling.
Area of Science:
- Immunology
- Structural Biology
- Molecular Recognition
Background:
- Toll-like receptors (TLRs) are key components of the innate immune system, recognizing pathogen-associated molecular patterns.
- TLR3 specifically recognizes double-stranded RNA (dsRNA), a hallmark of viral infections, through its ectodomain (ECD).
Purpose of the Study:
- To elucidate the structural basis of TLR3 ectodomain (ECD) binding to dsRNA.
- To understand the mechanism of dimer formation and its role in innate immune signal transduction.
- To identify common dimerization patterns across different TLRs.
Main Methods:
- X-ray crystallography was employed to determine the structure of the TLR3-ECD:dsRNA complex.
- Structural analysis focused on ligand binding sites, dimer interfaces, and C-terminal domain positioning.
Main Results:
- TLR3-ECDs form dimers that bind dsRNA oligonucleotides (≥45 bp) at two sites on a glycan-free lateral face.
- Intermolecular contacts between C-terminal domains stabilize the dimer, positioning C-termini closely for signal transduction.
- A conserved dimerization mechanism was observed in TLRs 1, 2, and 4 upon binding lipid ligands.
Conclusions:
- Pathogen-derived molecules binding to TLR-ECDs induce dimerization, bringing conserved glycan-free surfaces and C-termini together.
- This conserved dimerization mechanism is crucial for initiating innate immune responses across various TLRs.
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