The Molecular Structure of the Toll-Like Receptor 3 Ligand-Binding Domain

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-08, Vol.102 (31), p.10976-10980
• Main Authors: Bell, Jessica K., Botos, Istvan, Hall, Pamela R., Askins, Janine, Shiloach, Joseph, Segal, David M., Davies, David R.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Binding Sites; Biological Sciences; Crystallography, X-Ray; Crystals; Double stranded RNA; Humans; Immune system; Immunology; In Vitro Techniques; Ligands; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Models, Molecular; Molecular Sequence Data; Molecular structure; Molecules; Pathogens; Polysaccharides; Protein Conformation; Protein Structure, Tertiary; Proteins; Receptors; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA; RNA, Double-Stranded - chemistry; RNA, Double-Stranded - metabolism; Signal transduction; Sulfates; Toll-Like Receptor 3; Toll-Like Receptors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0505077102

Innate immunity is the first line of defense against invading pathogens. Toll-like receptors (TLRs) act as sentinels of the innate immune system, sensing a variety of ligands from lipopolysaccharide to flagellin to dsRNA through their ligand-binding domain that is composed of leucine-rich repeats (LRRs). Ligand binding initiates a signaling cascade that leads to the up-regulation of inflammation mediators. In this study, we have expressed and crystallized the ectodomain (ECD) of human TLR3, which recognizes dsRNA, a molecular signature of viruses, and have determined the molecular structure to 2.4-Å resolution. The overall horseshoe-shaped structure of the TLR3-ECD is formed by 23 repeating LRRs that are capped at each end by specialized non-LRR domains. The extensive β-sheet on the molecule's concave surface forms a platform for several modifications, including insertions in the LRRs and 11 N-linked glycans. The TLR3-ECD structure indicates how LRR loops can establish distinct pathogen recognition receptors.