Toll-Interleukin 1 Receptor (TIR) Domain-Containing Adapter Protein

2012 ◽  
pp. 1884-1884
Author(s):  
João Gonçalves ◽  
Helena Soares ◽  
Norman L. Eberhardt ◽  
Sarah C. R. Lummis ◽  
David R. Soto-Pantoja ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Adapter Protein ◽  
Tir Domain

scholarly journals Targeting Toll-like Receptor (TLR) Signaling by Toll/Interleukin-1 Receptor (TIR) Domain-containing Adapter Protein/MyD88 Adapter-like (TIRAP/Mal)-derived Decoy Peptides

2012 ◽  
Vol 287 (29) ◽  
pp. 24641-24648 ◽  
Author(s):  
Leah A. Couture ◽  
Wenji Piao ◽  
Lisa W. Ru ◽  
Stefanie N. Vogel ◽  
Vladimir Y. Toshchakov
Keyword(s):  
Interleukin 1 ◽  
Adapter Protein ◽  
Toll Like Receptor ◽  
Tlr Signaling ◽  
Tir Domain

scholarly journals TIRP, a Novel Toll/Interleukin-1 receptor (TIR) Domain-containing Adapter Protein Involved in TIR Signaling

2003 ◽  
Vol 278 (27) ◽  
pp. 24526-24532 ◽  
Author(s):  
Liang-Hua Bin ◽  
Liang-Guo Xu ◽  
Hong-Bing Shu
Keyword(s):  
Interleukin 1 ◽  
Adapter Protein ◽  
Tir Domain

The role of MyD88-like adapters in Toll-like receptor signal transduction

2003 ◽  
Vol 31 (3) ◽  
pp. 643-647 ◽  
Author(s):  
L.A.J. O'Neill
Keyword(s):  
Signal Transduction ◽  
Interleukin 1 ◽  
Adapter Proteins ◽  
Adapter Protein ◽  
Tir Domain ◽  
Receptor Signal ◽  
The Subject ◽  
Tir Domains ◽  
Tlr Signalling

Signal-transduction pathways activated by Toll-like receptors (TLRs) have been the subject of intense investigation because of the key role played by TLRs in the recognition and elimination of microbes. Signalling is initiated by a domain termed the Toll/interleukin-1 (IL-1) receptor (TIR) domain that occurs on the cytosolic face of TLRs. This recruits, via homotypic interactions, adapter proteins that contain TIR domains. Three such adapter proteins have been discovered to date, and have been named MyD88, Mal [MyD88 adapter-like; also known as TIRAP (TIR domain-containing adapter protein)] and Trif (TIR-domain-containing adapter inducing interferon-β). Differences are emerging between TLRs in terms of which adapter is recruited by which TLR. This may lead to specificities in TLR signalling, with pathways being triggered that are specific for the elimination of the invading microbe. However, signals that separate Mal from MyD88 have yet to emerge, although biochemical differences between the two proteins imply that each will have a specific function.

scholarly journals Modulation of microtubule dynamics by a TIR domain protein from the intracellular pathogen Brucella melitensis

2011 ◽  
Vol 439 (1) ◽  
pp. 79-83 ◽  
Author(s):  
Girish K. Radhakrishnan ◽  
Jerome S. Harms ◽  
Gary A. Splitter
Keyword(s):  
Brucella Melitensis ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Microtubule Dynamics ◽  
Innate Immune Responses ◽  
Tir Domain ◽  
Microtubule Stabilization ◽  
Loop Region ◽  
Microtubule Formation ◽  
Domain Protein

TIR (Toll/interleukin-1 receptor) domain-containing proteins play a crucial role in innate immunity in eukaryotes. Brucella is a highly infectious intracellular bacterium that encodes a TIR domain protein (TcpB) to subvert host innate immune responses to establish a beneficial niche for pathogenesis. TcpB inhibits NF-κB (nuclear factor κB) activation and pro-inflammatory cytokine secretions mediated by TLR (Toll-like receptor) 2 and TLR4. In the present study, we have demonstrated that TcpB modulates microtubule dynamics by acting as a stabilization factor. TcpB increased the rate of nucleation as well as the polymerization phases of microtubule formation in a similar manner to paclitaxel. TcpB could efficiently inhibit nocodazole- or cold-induced microtubule disassembly. Microtubule stabilization by TcpB is attributed to the BB-loop region of the TIR domain, and a point mutation affected the microtubule stabilization as well as the TLR-suppression properties of TcpB.

scholarly journals Induced proximity of a TIR signaling domain on a plant-mammalian NLR chimera activates defense in plants

2020 ◽  
Vol 117 (31) ◽  
pp. 18832-18839 ◽  
Author(s):  
Zane Duxbury ◽  
Shanshan Wang ◽  
Craig I. MacKenzie ◽  
Jeannette L. Tenthorey ◽  
Xiaoxiao Zhang ◽  
...  
Keyword(s):  
Plant Defense ◽  
Interleukin 1 ◽  
Coiled Coil ◽  
Leucine Rich Repeat ◽  
In Planta ◽  
Tir Domain ◽  
Signaling Mechanisms ◽  
Signaling Domain ◽  
Resistance Protein ◽  
Signaling Domains

Plant and animal intracellular nucleotide-binding, leucine-rich repeat (NLR) immune receptors detect pathogen-derived molecules and activate defense. Plant NLRs can be divided into several classes based upon their N-terminal signaling domains, including TIR (Toll-like, Interleukin-1 receptor, Resistance protein)- and CC (coiled-coil)-NLRs. Upon ligand detection, mammalian NAIP and NLRC4 NLRs oligomerize, forming an inflammasome that induces proximity of its N-terminal signaling domains. Recently, a plant CC-NLR was revealed to form an inflammasome-like hetero-oligomer. To further investigate plant NLR signaling mechanisms, we fused the N-terminal TIR domain of several plant NLRs to the N terminus of NLRC4. Inflammasome-dependent induced proximity of the TIR domain in planta initiated defense signaling. Thus, induced proximity of a plant TIR domain imposed by oligomerization of a mammalian inflammasome is sufficient to activate authentic plant defense. Ligand detection and inflammasome formation is maintained when the known components of the NLRC4 inflammasome is transferred across kingdoms, indicating that NLRC4 complex can robustly function without any additional mammalian proteins. Additionally, we found NADase activity of a plant TIR domain is necessary for plant defense activation, but NADase activity of a mammalian or a bacterial TIR is not sufficient to activate defense in plants.

Pococurante (Poc): An ENU-Induced Missense Mutation of MyD88 with Selective Effects on TLR Signal Transduction.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 649-649
Author(s):  
Zhengfan Jiang ◽  
Chenglong Li ◽  
Louis Shamel ◽  
Arthur Olson ◽  
Bruce Beutler
Keyword(s):  
Signal Transduction ◽  
Interleukin 1 ◽  
Adaptor Protein ◽  
Structural Diversity ◽  
Lipoteichoic Acid ◽  
Protein Docking ◽  
Structural Basis ◽  
Cpg Dna ◽  
Cpg Dinucleotides ◽  
Tir Domain

Abstract Toll-like receptors (TLRs) are key sensors of the innate immune system, and individual TLRs respond to specific molecules derived from microbes. MyD88 is a Toll/Interleukin-1/Resistance (TIR) domain-containing adaptor protein required for signaling by all TLRs except TLR3. While the structural basis of association between MyD88 and TIR-domain receptors is obscure, MyD88-deficient mice show no responses to bacterial flagellin, peptidoglycan (PGN), lipoteichoic acid (LTA), bacterial lipopeptides such as PAM2CSK4, PAM3CSK4 and R- or S-MALP-2, DNA bearing unmethylated CpG dinucleotides (CpG DNA), or Resiquimod (RSQ). Using germline ENU mutagenesis, we have produced a large number of phenotypic variants that have abnormal TLR signaling. We now report the identification of a new mutation called Pococurante (Poc), originally detected in screening because macrophages from this mouse showed no response to the tri-acylated lipopeptide PAM3CSK4, the di-acylated lipopeptide S-MALP-2, LTA, CpG DNA, RSQ, and a markedly reduced response to LPS: the ligands for TLRs 2/1, 2/6, 9, 7 and 4 respectively. They also had no response to interleukin-1, a cytokine that signals by way of a MyD88-dependent TIR domain receptor. However, Poc mice showed a normal response to PGN, as well as R-MALP-2 and PAM2CSK4 lipopeptides. The latter three ligands are sensed in a TLR2-dependent, MyD88-dependent fashion. The Poc phenotype was ascribed to a point mutation of MyD88 affecting a surface residue (I179N). Because the mutation is discriminatory, permitting MyD88 to carry a signal from some TIR domain receptors but not others, we infer that it resides at the receptor:adaptor signaling interface. A new model of TIR receptor:adaptor interaction is proposed on the basis of docking studies that take account of the Poc phenotype, made using the protein-protein docking program SURFDOCK. We note that S-MALP-2 is dependent upon TLR2/6 heterodimers, while PAM3CSK4 sensing depends upon TLR2/1 heterodimers. Since the Poc mutation forbids detection of both these ligands while it allows detection of PAM2CSK4 and R-MALP-2, it may be inferred that TLR2 signal transduction entails greater structural diversity than was previously supposed. The involvement of TLR2 homodimers, or the incorporation of subunits yet unknown into the receptor complex, cannot be excluded.

Signalling networks, inflammation and innate immunity

2003 ◽  
Vol 31 (6) ◽  
pp. 1462-1471 ◽  
Author(s):  
S.K. Dower ◽  
E.E. Qwarnstrom
Keyword(s):  
Real Time ◽  
Fluorescent Protein ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Biological Significance ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Screening Methods ◽  
Expression Screening ◽  
Tir Domain

We have been analysing the signalling systems that couple to receptors of the TIR (Toll/interleukin-1 receptor) family, which signal through a common cytoplasm region; the TIR domain. These systems are of both practical and fundamental biological significance, being central to the pathogenesis of chronic inflammatory diseases such as atherosclerosis, to host defence throughout the biological world, and are ancient in the context of life on earth, having originated more than 1 billion years ago: prior to the divergence of plants and animals. TIR domain receptors couple to at least two sets of well-characterized pathways: those leading to the activation of inhibitory κB kinase complexes/nuclear factor κB, and those leading to the activation of mitogen-activated protein kinase/AP-1/ATF-2 etc. We have been investigating these systems using a combination of expression screening methods to identify new components, and real-time green fluorescent protein-based techniques to observe execution of signalling programmes in real time. Our data reveal that there is a very large level of cell-to-cell variation in signal programme execution even in clonal populations and that at least one mechanism for dealing with this heterogeneity is the assembly of signal transduction components into large multiprotein complexes.

scholarly journals Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling

2017 ◽  
Vol 114 (32) ◽  
pp. E6480-E6489 ◽  
Author(s):  
Mark M. Hughes ◽  
Peter Lavrencic ◽  
Rebecca C. Coll ◽  
Thomas Ve ◽  
Dylan G. Ryan ◽  
...  
Keyword(s):  
Solution Structure ◽  
Interleukin 1 ◽  
Structural Rearrangement ◽  
Dominant Negative ◽  
Reduced Form ◽  
Negative Effects ◽  
Tir Domain ◽  
Downstream Target ◽  
Loop Region ◽  
Tlr4 Ligand

MyD88 adaptor-like (MAL) is a critical protein in innate immunity, involved in signaling by several Toll-like receptors (TLRs), key pattern recognition receptors (PRRs). Crystal structures of MAL revealed a nontypical Toll/interleukin-1 receptor (TIR)-domain fold stabilized by two disulfide bridges. We therefore undertook a structural and functional analysis of the role of reactive cysteine residues in the protein. Under reducing conditions, the cysteines do not form disulfides, but under oxidizing conditions they are highly amenable to modification. The solution structure of the reduced form of the MAL TIR domain, determined by NMR spectroscopy, reveals a remarkable structural rearrangement compared with the disulfide-bonded structure, which includes the relocation of a β-strand and repositioning of the functionally important “BB-loop” region to a location more typical for TIR domains. Redox measurements by NMR further reveal that C91 has the highest redox potential of all cysteines in MAL. Indeed, mass spectrometry revealed that C91 undergoes glutathionylation in macrophages activated with the TLR4 ligand lipopolysaccharide (LPS). The C91A mutation limits MAL glutathionylation and acts as a dominant negative, blocking the interaction of MAL with its downstream target MyD88. The H92P mutation mimics the dominant-negative effects of the C91A mutation, presumably by preventing C91 glutathionylation. The MAL C91A and H92P mutants also display diminished degradation and interaction with interleukin-1 receptor-associated kinase 4 (IRAK4). We conclude that in the cell, MAL is not disulfide-bonded and requires glutathionylation of C91 for signaling.

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