Structure of the Toll/Interleukin-1 Receptor (TIR) Domain of the B-cell Adaptor That Links Phosphoinositide Metabolism with the Negative Regulation of the Toll-like Receptor (TLR) Signalosome.

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.