Structural Basis of TLR5-flagellin Recognition and Signaling

Science. 2012 Feb 17;335(6070):859-64. doi: 10.1126/science.1215584.

Abstract

Toll-like receptor 5 (TLR5) binding to bacterial flagellin activates signaling through the transcription factor NF-κB and triggers an innate immune response to the invading pathogen. To elucidate the structural basis and mechanistic implications of TLR5-flagellin recognition, we determined the crystal structure of zebrafish TLR5 (as a variable lymphocyte receptor hybrid protein) in complex with the D1/D2/D3 fragment of Salmonella flagellin, FliC, at 2.47 angstrom resolution. TLR5 interacts primarily with the three helices of the FliC D1 domain using its lateral side. Two TLR5-FliC 1:1 heterodimers assemble into a 2:2 tail-to-tail signaling complex that is stabilized by quaternary contacts of the FliC D1 domain with the convex surface of the opposing TLR5. The proposed signaling mechanism is supported by structure-guided mutagenesis and deletion analyses on CBLB502, a therapeutic protein derived from FliC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Dimerization
  • Flagellin / chemistry*
  • Flagellin / metabolism
  • Models, Molecular
  • Mutagenesis
  • Protein Conformation
  • Salmonella enterica
  • Signal Transduction*
  • Structure-Activity Relationship
  • Toll-Like Receptor 5 / chemistry*
  • Toll-Like Receptor 5 / genetics
  • Toll-Like Receptor 5 / metabolism
  • Zebrafish
  • Zebrafish Proteins / chemistry*
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism

Substances

  • Toll-Like Receptor 5
  • Zebrafish Proteins
  • Flagellin

Associated data

  • PDB/3V44
  • PDB/3V47