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Structure of the TIR domain of BCAP which links phosphoinositide metabolism with the negative regulation of the TLR signalosome

Research paper by Samer Halabi, Eiki Sekine, Brett Verstack, Nicholas J. Gay, Martin C. Moncrieffe

Indexed on: 03 Dec '16Published on: 01 Dec '16Published in: Journal of Biological Chemistry



Abstract

Ligand binding to Toll-like receptors (TLRs) results in dimerization of their cytosolic TIR domains and recruitment of post-receptor signal transducers into a complex signalosome. TLR activation leads to the production of transcription factors, pro-inflammatory molecules and the activation of Phosphoinositide 3-kinases (PI3K) in a process that requires the multi-modular B-cell Adaptor for Phosphoinositide 3-kinase (BCAP). BCAP has a sequence previously proposed as a "cryptic" TIR domain. Here, we present the structure of the N-terminal region of human BCAP and show that it possesses a canonical TIR-fold. Dimeric BCAP associates with the TIR domains of TLR2/4 and Mal/TIRAP suggesting that it is recruited to the TLR signalosome by multitypic TIR-TIR interactions. BCAP also interacts with the p85 subunit of PI3K and phospholipase Cγ, enzymes that deplete plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2) and these interactions provide a molecular explanation for BCAP mediated down-regulation of inflammatory signalling.