title: The dsRNA binding site of human Toll-like receptor 3.
abstract: Pathogen recognition by Toll-like receptors (TLRs) initiates innate immune responses that are essential for inhibiting pathogen dissemination and for the development of acquired immunity. The TLRs recognize pathogens with their N-terminal ectodomains (ECD), but the molecular basis for this recognition is not known. Recently we reported the x-ray structure for unliganded TLR3-ECD; however, it has proven difficult to obtain a crystal structure of TLR3 with its ligand, dsRNA. We have now located the TLR3 ligand binding site by mutational analysis. More than 50 single-residue mutations have been generated throughout the TLR3-ECD, but only two, H539E and N541A, resulted in the loss of TLR3 activation and ligand binding functions. These mutations locate the dsRNA binding site on the glycan-free, lateral surface of TLR3 toward the C terminus and suggest a model for dsRNA binding and TLR3 activation.
authors.affiliation: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, and Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Bell
authors.forename: Janine
authors.initials: J
authors.lastname: Askins
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Hall
authors.forename: David R
authors.initials: DR
authors.lastname: Davies
authors.forename: David M
authors.initials: DM
authors.lastname: Segal
mesh_terms: D001665:Binding Sites; D006801:Humans; D000090263:Leucine-Rich Repeat Proteins; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009690:Nucleic Acid Conformation; D011487:Protein Conformation; D011506:Proteins / Q000235:genetics; D012330:RNA, Double-Stranded / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013431:Sulfates / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D000090263:Leucine-Rich Repeat Proteins; D008024:Ligands; D011506:Proteins; D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; D013431:Sulfates; D051196:Toll-Like Receptor 3