Title |
Mechanism of Bacterial Interference with TLR4 Signaling by Brucella Toll/Interleukin-1 Receptor Domain-containing Protein TcpB*
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Published in |
Journal of Biological Chemistry, November 2013
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DOI | 10.1074/jbc.m113.523274 |
Pubmed ID | |
Authors |
Mohammed Alaidarous, Thomas Ve, Lachlan W. Casey, Eugene Valkov, Daniel J. Ericsson, M. Obayed Ullah, Mark A. Schembri, Ashley Mansell, Matthew J. Sweet, Bostjan Kobe |
Abstract |
Upon activation of Toll-like receptors (TLRs), cytoplasmic Toll/interleukin-1 receptor (TIR) domains of the receptors undergo homo- or heterodimerization. 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 with 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. |
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Professor | 4 | 7% |
Professor > Associate Professor | 4 | 7% |
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Veterinary Science and Veterinary Medicine | 2 | 3% |
Other | 4 | 7% |
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