5for
From Proteopedia
Cryptic TIR
Structural highlights
FunctionBCAP_HUMAN Signaling adapter that contributes to B-cell development by linking B-cell receptor (BCR) signaling to the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway. Has a complementary role to the BCR coreceptor CD19, coupling BCR and PI3K activation by providing a docking site for the PI3K subunit PIK3R1. Alternatively, links Toll-like receptor (TLR) signaling to PI3K activation, a process preventing excessive inflammatory cytokine production. Also involved in the activation of PI3K in natural killer cells. May be involved in the survival of mature B-cells via activation of REL.[1] Publication Abstract from PubMedLigand 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 Cgamma, 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. Structure of the TIR domain of BCAP which links phosphoinositide metabolism with the negative regulation of the TLR signalosome.,Halabi S, Sekine E, Verstack B, Gay NJ, Moncrieffe MC J Biol Chem. 2016 Dec 1. pii: jbc.M116.761528. PMID:27909057[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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