Structural Basis of Toll-Like Receptor 3 Signaling with Double-Stranded RNA
Open accessAbstract
Toll-like receptor 3 (TLR3) recognizes double-stranded RNA (dsRNA), a molecular signature of most viruses, and triggers inflammatory responses that prevent viral spread. TLR3 ectodomains (ECDs) dimerize on oligonucleotides of at least 40 to 50 base pairs in length, the minimal length required for signal transduction. To establish the molecular basis for ligand binding and signaling, we determined the crystal structure of a complex between two mouse TLR3-ECDs and dsRNA at 3.4 angstrom resolution. Each TLR3-ECD binds dsRNA at two sites located at opposite ends of the TLR3 horseshoe, and an intermolecular contact between the two TLR3-ECD C-terminal domains coordinates and stabilizes the dimer. This juxtaposition could mediate downstream signaling by dimerizing the cytoplasmic Toll interleukin-1 receptor (TIR) domains. The overall shape of the TLR3-ECD does not change upon binding to dsRNA.
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Long double-stranded regions may induce unwanted innate immune responses.
“In addition, it has been revealed that long double-stranded regions may induce unwanted innate immune responses by previous studies27,54,55.”
From Algorithm for optimized mRNA design improves stability and immunogenicity (2023) · cites this paper as [27]
The Abstract (p. 379) says dsRNA of at least 40–50 base pairs enables TLR3 signaling and that TLR3 activation triggers inflammatory responses. This supports the possibility of an innate immune response to long double-stranded regions, but the paper describes those responses as preventing viral spread, not as unwanted. (LLM, conf=0.85)
Experimental — accuracy not yet measuredLong helices may elicit unwanted innate immune responses.
“It has also been suggested that long helices may elicit unwanted innate immune responses27, so we avoided them in our designs.”
From Algorithm for optimized mRNA design improves stability and immunogenicity (2023) · cites this paper as [27]
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- Authors
- Liu, L., Botos, I., Wang, Y., Leonard, J. N., Shiloach, J., Segal, D. M., & Davies, D. R.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Davies, David R.
- Venue
- Science
- Published
- 2008-04-18
- Volume
- 320
- Issue
- 5874
- Pages
- 379-381
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2761030
- OpenAlex
- W2150736048
- Cited by
- 733
- References
- 15
- Citations by year
- 2026: 20 · 2025: 23 · 2024: 24 · 2023: 31 · 2022: 29 · 2021: 32 · 2020: 35 · 2019: 36 · 2018: 42 · 2017: 32 · 2016: 39 · 2015: 33 · 2014: 52 · 2013: 51 · 2012: 57
- FWCI
- 27.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (Z01BC009254)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- TLR3, double-stranded RNA, ligand binding, receptor dimerization, TIR domain, crystal structure, innate immunity, antiviral signaling, oligonucleotide length
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Humans, Ligands, Models, Molecular, Molecular Sequence Data, Nucleic Acid Conformation, Protein Conformation, RNA, Double-Stranded, Signal Transduction, NF-kappa B, Protein Structure, Tertiary, Crystallography, X-Ray, Dimerization, Mutant Proteins, Toll-Like Receptor 3, Mice
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