title: 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 Toll/interleukin-1 receptor (TIR) domains and recruitment of post-receptor signal transducers into a complex signalosome. TLR activation leads to the production of transcription factors and pro-inflammatory molecules and the activation of phosphoinositide 3-kinases (PI3K) in a process that requires the multimodular 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 signaling.
authors.affiliation: From the Department of Biochemistry, Cambridge University, Cambridge CB2 1GA, United Kingdom.
authors.forename: Samer
authors.initials: S
authors.lastname: Halabi
authors.affiliation: From the Department of Biochemistry, Cambridge University, Cambridge CB2 1GA, United Kingdom.
authors.forename: Eiki
authors.initials: E
authors.lastname: Sekine
authors.affiliation: From the Department of Biochemistry, Cambridge University, Cambridge CB2 1GA, United Kingdom.
authors.forename: Brett
authors.initials: B
authors.lastname: Verstak
authors.affiliation: From the Department of Biochemistry, Cambridge University, Cambridge CB2 1GA, United Kingdom njg11@cam.ac.uk.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Gay
authors.affiliation: From the Department of Biochemistry, Cambridge University, Cambridge CB2 1GA, United Kingdom mcm35@cam.ac.uk.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Moncrieffe
mesh_terms: D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains; D055503:Protein Multimerization; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C569026:MAL protein, human; D008562:Membrane Glycoproteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; C520779:ODF2L protein, human; D019269:Phosphatidylinositol 4,5-Diphosphate; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D019869:Phosphatidylinositol 3-Kinases
keywords: BCAP; BCAP adaptor; MAL/TIRAP; PI3 kinase; PLCγ2; TIR domain; Toll-like receptor; Toll-like receptor (TLR); crystal structure; pathway crosstalk; phosphatidylinositide 3-kinase (PI 3-kinase); phosphatidylinositol 4,5-bisphosphate; phospholipase C