Scaffolding role of TcpB in disrupting TLR4‐Mal interactions: Three to tango

Toll/interleukin‐1 like receptors (TLRs) are membrane‐spanning proteins crucially involved in innate immunity. On activation, the cytoplasmic toll/interleukin‐1 receptor (TIR) domains of these receptors undergo homo‐ or heterodimerization. Brucella sp. are bacterial pathogens that affect the immune...

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Bibliographic Details
Published in:Journal of cellular biochemistry 2019-03, Vol.120 (3), p.3455-3458
Main Authors: Saqib, Uzma, Baig, Mirza S
Format: Article
Language:English
Subjects:
Activation
Anchoring
Attenuation
Cytokines
Disruption
Immune system
Immunity
Inflammation
Innate immunity
Interleukins
Mal
Proteins
protein‐protein interaction (PPI)
Receptors
Scaffolding
Signal transduction
Signaling
structural modeling
TcpB
TLR4 protein
Toll-like receptors
toll/interleukin‐1 like receptor 4 (TLR4)
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Summary:Toll/interleukin‐1 like receptors (TLRs) are membrane‐spanning proteins crucially involved in innate immunity. On activation, the cytoplasmic toll/interleukin‐1 receptor (TIR) domains of these receptors undergo homo‐ or heterodimerization. Brucella sp. are bacterial pathogens that affect the immune system by suppressing the TLR signaling pathway. They enact this by encoding a TIR domain–containing protein, TcpB, which suppresses NF‐κB activation and proinflammatory cytokine secretion mediated by TLR4 receptors. TcpB has been shown to target the Mal‐mediated pathway to suppress TLR signaling. The recent identification of its mechanism of interference with TLR4 signaling involving Mal prompted us to further study the structural aspects of TcpB binding with TLR4 and Mal. Our triprotein model displays the overall scaffolding role of TcpB in anchoring TLR4 and Mal thereby inhibiting their interaction leading to the attenuation of the TLR4 pathway. This novel work describes the structural aspects of Brucella TcpB binding to Mal and toll/interleukin‐1 like receptor 4 (TLR4), thereby inhibiting the TLR4 pathway. We understand that this study is the first of its kind and would throw light on how scaffolding by TcpB leads to the inhibition of TLR4‐Mal interaction critical for downstream inflammatory signaling.
ISSN:0730-2312
1097-4644
DOI:10.1002/jcb.27619