Structural Basis of Toll-Like Receptor 3 Signaling with Double-Stranded RNA

doi:10.1126/science.1155406

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Structural Basis of Toll-Like Receptor 3 Signaling with Double-Stranded RNA

Lin Liu,¹ Istvan Botos,¹ Yan Wang,² Joshua N. Leonard,² Joseph Shiloach,³ David M. Segal,² David R. Davies¹^*

Abstract: Toll-like receptor 3 (TLR3) recognizes double-stranded RNA (dsRNA),a molecular signature of most viruses, and triggers inflammatoryresponses that prevent viral spread. TLR3 ectodomains (ECDs)dimerize on oligonucleotides of at least 40 to 50 base pairsin 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 twomouse TLR3-ECDs and dsRNA at 3.4 angstrom resolution. Each TLR3-ECDbinds dsRNA at two sites located at opposite ends of the TLR3horseshoe, and an intermolecular contact between the two TLR3-ECDC-terminal domains coordinates and stabilizes the dimer. Thisjuxtaposition could mediate downstream signaling by dimerizingthe cytoplasmic Toll interleukin-1 receptor (TIR) domains. Theoverall shape of the TLR3-ECD does not change upon binding todsRNA.

¹ Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
² Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD20892, USA.
³ Biotechnology Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

^* To whom correspondence should be addressed: david.davies{at}nih.gov

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