The Journal of Experimental Medicine
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Published online February 5, 2007
doi:10.1084/jem.20061400
The Journal of Experimental Medicine, Vol. 204, No. 2, 393-403
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Andersen-Nissen et al.
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ARTICLE

 A conserved surface on Toll-like receptor 5 recognizes bacterial flagellin

Erica Andersen-Nissen1,2, Kelly D. Smith1,3, Richard Bonneau4,5, Roland K. Strong2,6, and Alan Aderem1

1 Institute for Systems Biology, Seattle, WA 98103
2 Department of Immunology and 3 Department of Pathology, University of Washington, Seattle, WA 98195
4 Biology Department and 5 Courant Computer Science Department, New York University, New York, NY 10003
6 Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109

CORRESPONDENCE Alan Aderem: aderem{at}systemsbiology.org

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 ß sheets results in TLR activation and provide a new framework for understanding TLR–agonist interactions.

Abbreviations used: HA, hemagglutinin; LRR, leucine-rich repeat; TLR, Toll-like receptor.


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