Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 204, Issue 2, Pages 393-403Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20061400
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Funding
- NIAID NIH HHS [R01 AI52286, U54 AI054523, U54 AI54523, R01 AI052286, R01 AI48675, R01 AI048675, R01 AI062859] Funding Source: Medline
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The molecular basis for Toll-like receptor (TLR) recognition of microbial ligands is unknown. We demonstrate that mouse and human TLR5 discriminate between different flagellins, and we use this difference to map the flagellin recognition site on TLR5 to 228 amino acids of the extracellular domain. Through molecular modeling of the TLR5 ectodomain, we identify two conserved surface-exposed regions. Mutagenesis studies demonstrate that naturally occurring amino acid variation in TLR5 residue 268 is responsible for human and mouse discrimination between flagellin molecules. Mutations within one conserved surface identify residues D295 and D367 as important for flagellin recognition. These studies localize flagellin recognition to a conserved surface on the modeled TLR5 structure, providing detailed analysis of the interaction of a TLR with its ligand. These findings suggest that ligand binding at the beta sheets results in TLR activation and provide a new framework for understanding TLR-agonist interactions.
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