Structural highlights
Publication Abstract from PubMedUpon 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. Mechanism of bacterial interference with TLR4 signaling by Brucella TIR-domain-containing protein TcpB.,Alaidarous M, Ve T, Casey LW, Valkov E, Ericsson DJ, Ullah MO, Schembri MA, Mansell A, Sweet MJ, Kobe B J Biol Chem. 2013 Nov 21. PMID:24265315[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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