4C7M

The crystal structure of TcpB or BtpA TIR domain

Summary for 4C7M

• Entry DOI: 10.2210/pdb4c7m/pdb
• Descriptor: Toll/interleukin-1 receptor domain-containing protein (2 entities in total)
• Functional Keywords: signaling protein, protein
• Biological source: Brucella melitensis
• Total number of polymer chains: 4
• Total formula weight: 60240.48

Authors

Alaidarous, M.,Ve, T.,Casey, L.W.,Valkov, E.,Ullah, M.O.,Schembri, M.A.,Mansell, A.,Sweet, M.J.,Kobe, B. (deposition date: 2013-09-23, release date: 2013-12-04, Last modification date: 2023-12-20)

Primary citation

Alaidarous, M.,Ve, T.,Casey, L.W.,Valkov, E.,Ericsson, D.J.,Ullah, M.O.,Schembri, M.A.,Mansell, A.,Sweet, M.J.,Kobe, B.
Mechanism of bacterial interference with TLR4 signaling by Brucella Toll/interleukin-1 receptor domain-containing protein TcpB.
J.Biol.Chem., 289:654-668, 2014

PubMed 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.

PubMed: 24265315
DOI: 10.1074/jbc.M113.523274

Experimental method

X-RAY DIFFRACTION (2.57 Å)