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Science 335 (6070): 859-864

Copyright © 2012 by the American Association for the Advancement of Science

Structural Basis of TLR5-Flagellin Recognition and Signaling

Sung-il Yoon,1 Oleg Kurnasov,2,* Venkatesh Natarajan,3,* Minsun Hong,1,* Andrei V. Gudkov,3,4 Andrei L. Osterman,2,{dagger} Ian A. Wilson1,5,{dagger}

Abstract: Toll-like receptor 5 (TLR5) binding to bacterial flagellin activates signaling through the transcription factor NF-{kappa}B 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.

1 Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
2 Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
3 Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
4 Cleveland BioLabs Inc., Buffalo, NY 14203, USA.
5 Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: wilson{at}scripps.edu (I.A.W.); osterman{at}sanfordburnham.org (A.L.O.)


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