title: Structural basis of TLR5-flagellin recognition and signaling.
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.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Sung-il
authors.initials: SI
authors.lastname: Yoon
authors.forename: Oleg
authors.initials: O
authors.lastname: Kurnasov
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Natarajan
authors.forename: Minsun
authors.initials: M
authors.lastname: Hong
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Osterman
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D019281:Dimerization; D005408:Flagellin / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D016296:Mutagenesis; D011487:Protein Conformation; D019779:Salmonella enterica; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D051198:Toll-Like Receptor 5 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D051198:Toll-Like Receptor 5; D029961:Zebrafish Proteins; D005408:Flagellin