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A second binding site for double-stranded RNA in TLR3 and consequences for interferon activation

Abstract

We show that substrate specificity of Toll-like receptor 3 (TLR3) is due to the presence of two binding sites in the ectodomain, separated by 50 Å. This corresponds to two turns of a double-stranded RNA duplex, allowing differentiation between nucleic acids in the A- or B-type conformation. We propose that there are different arrangements of TLR3 ectodomains along the double-stranded RNA that could modulate the strength of the interferon response.

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Figure 1: Two dsRNA binding sites on the TLR3 ectodomain are required for activation by dsRNA.
Figure 2: Secondary structure of nucleic acids regulates activation based on fit to the binding sites of the TLR3 ectodomain.
Figure 3: Different docking arrangements of the TLR3 ectodomain dimer along the RNA duplex are compatible with dimerization of the intracellular TIR domain.

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Acknowledgements

This work was funded by the Slovenian Research Agency. We would like to thank J. Hiscott (McGill University) for his kind gift of interferon-β luciferase reporter plasmid.

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Correspondence to Roman Jerala.

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Supplementary Figures 1–5 and Supplementary Methods (PDF 3939 kb)

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Pirher, N., Ivičak, K., Pohar, J. et al. A second binding site for double-stranded RNA in TLR3 and consequences for interferon activation. Nat Struct Mol Biol 15, 761–763 (2008). https://doi.org/10.1038/nsmb.1453

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