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 A. 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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