Structural basis of TLR5-flagellin recognition and signaling
- Authors
- Yoon, S.I., Kurnasov, O., Natarajan, V., Hong, M., Gudkov, A.V., and Osterman, A.L., and Wilson, I.A.
- ID
- ZDB-PUB-120223-13
- Date
- 2012
- Source
- Science (New York, N.Y.) 335(6070): 859-864 (Journal)
- Registered Authors
- Keywords
- none
- 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
- PubMed
- 22344444 Full text @ Science
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.