期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 2, 页码 654-668出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.523274
关键词
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资金
- National Health and Medical Research Council Grant [APP1003326]
- Ministry of Higher Education of Saudi Arabia
- Majmaah University (Al Majmaah, Saudi Arabia)
- Australian Research Council [FT100100662, FT100100657]
- National Health and Medical Research Council [APP1003470, APP1003325]
- Australian Research Council [FT100100657, FT100100662] Funding Source: Australian Research Council
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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