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The molecular structure of the TLR3 extracellular domain

Laboratory of Molecular Biology, National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, Maryland, USA

Istvan Botos

Laboratory of Molecular Biologyy, National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, Maryland, USA

Pamela R. Hall

Laboratory of Molecular Biologyy, National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, Maryland, USA

Janine Askins

Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

Joseph Shiloach

Biotechnology Unity, National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, Maryland, USA

David R. Davies

Laboratory of Molecular Biologyy, National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, Maryland, USA

David M. Segal

Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA, dave_segal{at}nih.gov

Toll-like receptors (TLRs), type I integral membrane receptors, recognize pathogen associated molecular patterns (PAMPs). PAMP recognition occurs via the N-terminal ectodomain (ECD) which initiates an inflammatory response that is mediated by the C-terminal cytosolic signaling domain. To understand the molecular basis of PAMP recognition, we have begun to define TLR—ECD structurally. We have solved the structure of TLR3-ECD, which recognizes dsRNA, a PAMP associated with viral pathogens. TLR3-ECD is a horseshoe-shaped solenoid composed of 23 leucine-rich repeats (LRRs). The regular LRR surface is disrupted by two insertions at LRR12 and LRR20 and 11 N-linked carbohydrates. Of note, one side of the ECD is carbohydrate-free and could form an interaction interface. We have shown that TLR3-ECD binds directly to pI:pC, a synthetic dsRNA ligand, but not to p(dI):p(dC). Without a TLR3—dsRNA complex structure, we can only speculate how ligand binds. Analysis of the unliganded structure reveals two patches of basic residues and two binding sites for phosphate backbone mimics, sulfate ions, that may be capable of recognizing ligand. Mutational and co-crystallization studies are currently underway to determine how TLR3 binds its ligand at the molecular level.

Key Words: Toll-like receptors • innate immunity • protein structure

Journal of Endotoxin Research, Vol. 12, No. 6, 375-378 (2006)
DOI: 10.1177/09680519060120060801


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