title: A conserved surface on Toll-like receptor 5 recognizes bacterial flagellin.
abstract: 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.
authors.affiliation: Institute for Systems Biology, Seattle, WA 98103, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Andersen-Nissen
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Smith
authors.forename: Richard
authors.initials: R
authors.lastname: Bonneau
authors.forename: Roland K
authors.initials: RK
authors.lastname: Strong
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
mesh_terms: D000818:Animals; D001419:Bacteria / Q000737:chemistry*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005408:Flagellin / Q000302:isolation & purification / Q000378:metabolism*; D014644:Genetic Variation; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008958:Models, Molecular; D016296:Mutagenesis; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013045:Species Specificity; D051198:Toll-Like Receptor 5 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D051198:Toll-Like Receptor 5; D005408:Flagellin