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*

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.

[1]  Martyn F. Symmons,et al.  Assembly and localization of Toll-like receptor signalling complexes , 2014, Nature Reviews Immunology.

[2]  A. Iwasaki,et al.  A Promiscuous Lipid-Binding Protein Diversifies the Subcellular Sites of Toll-like Receptor Signal Transduction , 2014, Cell.

[3]  N. Gay,et al.  An Alanine-to-Proline Mutation in the BB-Loop of TLR3 Toll/IL-1R Domain Switches Signalling Adaptor Specificity from TRIF to MyD88 , 2013, The Journal of Immunology.

[4]  Thomas Miethke,et al.  Crystal Structures of the Toll/Interleukin-1 Receptor (TIR) Domains from the Brucella Protein TcpB and Host Adaptor TIRAP Reveal Mechanisms of Molecular Mimicry* , 2013, The Journal of Biological Chemistry.

[5]  M. Alarcón‐Riquelme,et al.  BANK1 Controls CpG-Induced IL-6 Secretion via a p38 and MNK1/2/eIF4E Translation Initiation Pathway , 2013, The Journal of Immunology.

[6]  M. Kogut,et al.  Combined CpG and poly I:C stimulation of monocytes results in unique signaling activation not observed with the individual ligands. , 2013, Cellular signalling.

[7]  Philip R. Evans,et al.  How good are my data and what is the resolution? , 2013, Acta crystallographica. Section D, Biological crystallography.

[8]  M. Bernal-Quirós,et al.  BANK1 and BLK Act through Phospholipase C Gamma 2 in B-Cell Signaling , 2013, PloS one.

[9]  K. Okkenhaug.  Signaling by the phosphoinositide 3-kinase family in immune cells. , 2013, Annual review of immunology.

[10]  Paul D. Adams,et al.  Use of knowledge-based restraints in phenix.refine to improve macromolecular refinement at low resolution , 2012, Acta crystallographica. Section D, Biological crystallography.

[11]  Wei Hu,et al.  Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt , 2011, Proceedings of the National Academy of Sciences.

[12]  J. Hamerman,et al.  B-cell adaptor for PI3K (BCAP) negatively regulates Toll-like receptor signaling through activation of PI3K , 2011, Proceedings of the National Academy of Sciences.

[13]  Chih-yuan Chiang,et al.  Phospholipase Cγ-2 and Intracellular Calcium Are Required for Lipopolysaccharide-induced Toll-like Receptor 4 (TLR4) Endocytosis and Interferon Regulatory Factor 3 (IRF3) Activation* , 2011, The Journal of Biological Chemistry.

[14]  F. Granucci,et al.  CD14 Controls the LPS-Induced Endocytosis of Toll-like Receptor 4 , 2011, Cell.

[15]  F. DiMaio,et al.  Crystal structure of Toll-like receptor adaptor MAL/TIRAP reveals the molecular basis for signal transduction and disease protection , 2011, Proceedings of the National Academy of Sciences.

[16]  T. Yamazaki,et al.  A Requirement for the p85 PI3K Adapter Protein BCAP in the Protection of Macrophages from Apoptosis Induced by Endoplasmic Reticulum Stress , 2011, The Journal of Immunology.

[17]  B. Kobe,et al.  Structural and functional analysis of a plant resistance protein TIR domain reveals interfaces for self-association, signaling, and autoregulation. , 2011, Cell host & microbe.

[18]  J. Liu,et al.  Association of TIRAP (MAL) gene polymorhisms with susceptibility to tuberculosis in a Chinese population. , 2011, Genetics and molecular research : GMR.

[19]  M. Oyama,et al.  Identification of BCAP-(L) as a negative regulator of the TLR signaling-induced production of IL-6 and IL-10 in macrophages by tyrosine phosphoproteomics. , 2010, Biochemical and biophysical research communications.

[20]  G. Sheldrick,et al.  A magic triangle for experimental phasing of macromolecules. , 2008, Acta crystallographica. Section D, Biological crystallography.

[21]  T. Yamazaki,et al.  Enhanced NK-cell development and function in BCAP-deficient mice. , 2008, Blood.

[22]  P. Nordlund,et al.  The Crystal Structure of the Human Toll-like Receptor 10 Cytoplasmic Domain Reveals a Putative Signaling Dimer* , 2008, Journal of Biological Chemistry.

[23]  Karen N. Allen,et al.  research papers Acta Crystallographica Section D Biological , 2003 .

[24]  A. Yoshimura,et al.  Peptidoglycan and lipopolysaccharide activate PLCγ2, leading to enhanced cytokine production in macrophages and dendritic cells , 2008, Genes to cells : devoted to molecular & cellular mechanisms.

[25]  Giorgio Sirugo,et al.  A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis , 2007, Nature Genetics.

[26]  Anil Verma,et al.  Lysine Methylation as a Routine Rescue Strategy for Protein Crystallization , 2006, Structure.

[27]  Xueyuan Zhou,et al.  Ca2+- and Protein Kinase C-dependent Signaling Pathway for Nuclear Factor-κB Activation, Inducible Nitric-oxide Synthase Expression, and Tumor Necrosis Factor-α Production in Lipopolysaccharide-stimulated Rat Peritoneal Macrophages* , 2006, Journal of Biological Chemistry.

[28]  Kevin Cowtan,et al.  The Buccaneer software for automated model building. 1. Tracing protein chains. , 2006, Acta crystallographica. Section D, Biological crystallography.

[29]  R. Medzhitov,et al.  Phosphoinositide-Mediated Adaptor Recruitment Controls Toll-like Receptor Signaling , 2006, Cell.

[30]  S. Rhee,et al.  Mechanism of B-Cell Receptor-Induced Phosphorylation and Activation of Phospholipase C-γ2 , 2004, Molecular and Cellular Biology.

[31]  J. Khan,et al.  Crystal Structure of the Toll/Interleukin-1 Receptor Domain of Human IL-1RAPL* , 2004, Journal of Biological Chemistry.

[32]  J. D. Dal Porto,et al.  B cell antigen receptor signaling 101. , 2004, Molecular immunology.

[33]  M. Leptin,et al.  Isolation of proteins that interact with the signal transduction molecule Dof and identification of a functional domain conserved between Dof and vertebrate BCAP. , 2003, Journal of molecular biology.

[34]  A. Plückthun,et al.  Designed to be stable: Crystal structure of a consensus ankyrin repeat protein , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Liang Tong,et al.  An extensively associated dimer in the structure of the C713S mutant of the TIR domain of human TLR2. , 2002, Biochemical and biophysical research communications.

[36]  George M Sheldrick,et al.  Substructure solution with SHELXD. , 2002, Acta crystallographica. Section D, Biological crystallography.

[37]  Lewis C Cantley,et al.  The phosphoinositide 3-kinase pathway. , 2002, Science.

[38]  S. Akira,et al.  Essential Immunoregulatory Role for BCAP in B Cell Development and Function , 2002, The Journal of experimental medicine.

[39]  Katsuhiko Mikoshiba,et al.  BANK regulates BCR‐induced calcium mobilization by promoting tyrosine phosphorylation of IP3 receptor , 2002, The EMBO journal.

[40]  T. Kurosaki,et al.  Tyrosine phosphorylation of B-cell adaptor for phosphoinositide 3-kinase is required for Akt activation in response to CD19 engagement. , 2002, Blood.

[41]  T. Kurosaki,et al.  BCAP: the tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation. , 2000, Immunity.

[42]  L. Tong,et al.  Structural basis for signal transduction by the Toll/interleukin-1 receptor domains , 2000, Nature.

[43]  P. Schuck,et al.  Size-distribution analysis of macromolecules by sedimentation velocity ultracentrifugation and lamm equation modeling. , 2000, Biophysical journal.

[44]  M. Waterfield,et al.  Signalling through phosphoinositide 3-kinases: the lipids take centre stage. , 1999, Current opinion in cell biology.

[45]  Lewis C. Cantley,et al.  The Role of Phosphoinositide 3-Kinase Lipid Products in Cell Function* , 1999, The Journal of Biological Chemistry.

[46]  M. Affolter,et al.  The Drosophila protein Dof is specifically required for FGF signaling. , 1998, Molecular cell.

[47]  S. Harrison,et al.  Crystal structure of the breakpoint cluster region-homology domain from phosphoinositide 3-kinase p85 alpha subunit. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[48]  J F Gibrat,et al.  Surprising similarities in structure comparison. , 1996, Current opinion in structural biology.

[49]  J. Zou,et al.  Improved methods for building protein models in electron density maps and the location of errors in these models. , 1991, Acta crystallographica. Section A, Foundations of crystallography.

[50]  W. Weiss,et al.  Targeting the RTK-PI3K-mTOR axis in malignant glioma: overcoming resistance. , 2010, Current topics in microbiology and immunology.

[51]  R. Schiestl,et al.  High-efficiency yeast transformation using the LiAc/SS carrier DNA/PEG method , 2007, Nature Protocols.

[52]  Xueyuan Zhou,et al.  Ca 2-and Protein Kinase C-dependent Signaling Pathway for Nuclear Factor-B Activation , Inducible Nitric-oxide Synthase Expression , and Tumor Necrosis Factor-Production in Lipopolysaccharide-stimulated Rat Peritoneal Macrophages * , 2006 .

[53]  T. Kurosaki,et al.  BLNK: connecting Syk and Btk to calcium signals. , 2000, Immunity.

[54]  K Henrick,et al.  Electronic Reprint Biological Crystallography Secondary-structure Matching (ssm), a New Tool for Fast Protein Structure Alignment in Three Dimensions Biological Crystallography Secondary-structure Matching (ssm), a New Tool for Fast Protein Structure Alignment in Three Dimensions , 2022 .