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

J Biol Chem. 2017 Jan 13;292(2):652-660. doi: 10.1074/jbc.M116.761528. Epub 2016 Dec 1.

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.

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.

MeSH terms

  • Carrier Proteins / chemistry*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Humans
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / metabolism
  • Myelin and Lymphocyte-Associated Proteolipid Proteins / chemistry
  • Myelin and Lymphocyte-Associated Proteolipid Proteins / genetics
  • Myelin and Lymphocyte-Associated Proteolipid Proteins / metabolism
  • Phosphatidylinositol 3-Kinases
  • Phosphatidylinositol 4,5-Diphosphate / chemistry
  • Phosphatidylinositol 4,5-Diphosphate / genetics
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Protein Domains
  • Protein Multimerization*
  • Receptors, Interleukin-1 / chemistry
  • Receptors, Interleukin-1 / metabolism
  • Signal Transduction*
  • Toll-Like Receptor 2 / chemistry*
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / chemistry*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism

Substances

  • Carrier Proteins
  • MAL protein, human
  • Membrane Glycoproteins
  • Myelin and Lymphocyte-Associated Proteolipid Proteins
  • ODF2L protein, human
  • Phosphatidylinositol 4,5-Diphosphate
  • Receptors, Interleukin-1
  • TIRAP protein, human
  • TLR2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Phosphatidylinositol 3-Kinases

Associated data

  • PDB/1FYX
  • PDB/1O77