Mechanism of bacterial interference with TLR4 signaling by Brucella TIR-domain-containing protein TcpB

Alaidarous, Mohammed Abdullah, Ve, Thomas, Casey, Lachlan, Valkov, Eugene, Ericsson, Daniel, Obayed, Ullah, M., Schembri, Mark A., Mansell, Ashley, Sweet, Matthew J. and Kobe, Bostjan (2013) Mechanism of bacterial interference with TLR4 signaling by Brucella TIR-domain-containing protein TcpB. Journal of Biological Chemistry, 289 2: 654-668. doi:10.1074/jbc.M113.523274

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Author Alaidarous, Mohammed Abdullah
Ve, Thomas
Casey, Lachlan
Valkov, Eugene
Ericsson, Daniel
Obayed, Ullah, M.
Schembri, Mark A.
Mansell, Ashley
Sweet, Matthew J.
Kobe, Bostjan
Title Mechanism of bacterial interference with TLR4 signaling by Brucella TIR-domain-containing protein TcpB
Formatted title
Mechanism of bacterial interference with TLR4 signaling by Brucella TIR-domain-containing protein TcpB
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
Publication date 2013-11-21
Year available 2013
Sub-type Article (original research)
DOI 10.1074/jbc.M113.523274
Open Access Status File (Author Post-print)
Volume 289
Issue 2
Start page 654
End page 668
Total pages 15
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2014
Language eng
Abstract Upon activation of Toll-like receptors (TLRs), cytoplasmic Toll/interleukin-1 receptor (TIR) domains of the receptors undergo homo- or hetero-dimerization. This in turn leads to the recruitment of adaptor proteins, activation of transcription factors, and the secretion of pro-inflammatory cytokines. Recent studies have described the TIR-domain-containing protein from Brucella melitensis, TcpB (BtpA/Btp1), to be involved in virulence and suppression of host innate immune responses. TcpB interferes with TLR4 and TLR2 signaling pathways by a mechanism that remains controversial. In this study, we show using co-immunoprecipitation analyses that TcpB interacts with MAL, MyD88, and TLR4, but interferes only with the MAL:TLR4 interaction. We present the crystal structure of the TcpB TIR domain, which reveals significant structural differences in the loop regions compared to other TIR domain structures. We demonstrate that TcpB forms a dimer in solution, and the crystal structure reveals the dimerization interface, which we validate by mutagenesis and biophysical studies. Our study advances the understanding of the molecular mechanisms of host immunosuppression by bacterial pathogens.
Keyword Toll IL-1 receptor (TIR) domain
Toll-like receptors (TLR)
Innate immunity
Protein structure
Adaptor proteins
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online ahead of print: 21 November 2013.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
 
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Created: Tue, 17 Dec 2013, 10:06:17 EST by Susan Allen on behalf of Institute for Molecular Bioscience