Mechanism of Bacterial Interference with TLR4 Signaling by Brucella Toll/Interleukin-1 Receptor Domain-containing Protein TcpB

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Alaidarous, Mohammed
Ve, Thomas
Casey, Lachlan W
Valkov, Eugene
Ericsson, Daniel J
Ullah, M Obayed
Schembri, Mark A
Mansell, Ashley
Sweet, Matthew J
Kobe, Bostjan
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2014
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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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Journal of Biological Chemistry
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This research was originally published in Journal of Biological Chemistry (JBC). Mohammed Alaidarous et al., Mechanism of Bacterial Interference with TLR4 Signaling by Brucella Toll/Interleukin-1 Receptor Domain-containing Protein TcpB, Journal of Biological Chemistry (JBC) VOL. 289, NO. 2, pp. 654 –668, 2014. Copyright the American Society for Biochemistry and Molecular Biology. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive version.
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Chemical sciences
Biological sciences
Biochemistry and cell biology not elsewhere classified
Biomedical and clinical sciences
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