Publication Date:
2012-02-22
Description:
Toll-like receptor 5 (TLR5) binding to bacterial flagellin activates signaling through the transcription factor NF-kappaB 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406927/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406927/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yoon, Sung-il -- Kurnasov, Oleg -- Natarajan, Venkatesh -- Hong, Minsun -- Gudkov, Andrei V -- Osterman, Andrei L -- Wilson, Ian A -- AI042266/AI/NIAID NIH HHS/ -- R01 AI042266/AI/NIAID NIH HHS/ -- R01 AI042266-05/AI/NIAID NIH HHS/ -- R01 AI080446/AI/NIAID NIH HHS/ -- R01 AI080446-05/AI/NIAID NIH HHS/ -- RC2 AI087616/AI/NIAID NIH HHS/ -- RC2 AI087616-02/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2012 Feb 17;335(6070):859-64. doi: 10.1126/science.1215584.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22344444" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Crystallography, X-Ray
;
Dimerization
;
Flagellin/*chemistry/metabolism
;
Models, Molecular
;
Mutagenesis
;
Protein Conformation
;
Salmonella enterica
;
*Signal Transduction
;
Structure-Activity Relationship
;
Toll-Like Receptor 5/*chemistry/genetics/metabolism
;
Zebrafish
;
Zebrafish Proteins/*chemistry/genetics/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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