+Open data
-Basic information
Entry | Database: PDB / ID: 5uzb | ||||||
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Title | Cryo-EM structure of the MAL TIR domain filament | ||||||
Components | Toll/interleukin-1 receptor domain-containing adapter protein | ||||||
Keywords | IMMUNE SYSTEM / TIR domain / adaptor proteins / TLR signaling / homotypic protein interactions | ||||||
Function / homology | Function and homology information positive regulation of interleukin-15 production / TIRAP-dependent toll-like receptor 4 signaling pathway / regulation of interferon-beta production / cellular response to bacterial lipopeptide / positive regulation of toll-like receptor 3 signaling pathway / Toll-like receptor 4 binding / positive regulation of toll-like receptor 2 signaling pathway / Toll-like receptor 2 binding / positive regulation of toll-like receptor 4 signaling pathway / positive regulation of chemokine (C-X-C motif) ligand 1 production ...positive regulation of interleukin-15 production / TIRAP-dependent toll-like receptor 4 signaling pathway / regulation of interferon-beta production / cellular response to bacterial lipopeptide / positive regulation of toll-like receptor 3 signaling pathway / Toll-like receptor 4 binding / positive regulation of toll-like receptor 2 signaling pathway / Toll-like receptor 2 binding / positive regulation of toll-like receptor 4 signaling pathway / positive regulation of chemokine (C-X-C motif) ligand 1 production / myeloid cell differentiation / positive regulation of chemokine (C-X-C motif) ligand 2 production / positive regulation of neutrophil chemotaxis / MyD88 deficiency (TLR2/4) / MyD88-dependent toll-like receptor signaling pathway / IRAK4 deficiency (TLR2/4) / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / toll-like receptor 4 signaling pathway / 3'-UTR-mediated mRNA stabilization / regulation of innate immune response / extrinsic component of cytoplasmic side of plasma membrane / cellular response to lipoteichoic acid / endocytic vesicle / signaling adaptor activity / positive regulation of B cell proliferation / phosphatidylinositol-4,5-bisphosphate binding / positive regulation of interleukin-12 production / positive regulation of interleukin-8 production / protein kinase C binding / positive regulation of JNK cascade / ruffle membrane / positive regulation of protein-containing complex assembly / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / positive regulation of NF-kappaB transcription factor activity / protein-macromolecule adaptor activity / positive regulation of canonical NF-kappaB signal transduction / ER-Phagosome pathway / response to lipopolysaccharide / positive regulation of ERK1 and ERK2 cascade / cell surface receptor signaling pathway / molecular adaptor activity / defense response to Gram-positive bacterium / inflammatory response / innate immune response / cell surface / identical protein binding / plasma membrane / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 7 Å | ||||||
Authors | Ve, T. / Vajjhala, P.R. / Hedger, A. / Croll, T. / DiMaio, F. / Horsefield, S. / Yu, X. / Lavrencic, P. / Hassan, Z. / Morgan, G.P. ...Ve, T. / Vajjhala, P.R. / Hedger, A. / Croll, T. / DiMaio, F. / Horsefield, S. / Yu, X. / Lavrencic, P. / Hassan, Z. / Morgan, G.P. / Mansell, A. / Mobli, M. / O'Carrol, A. / Chauvin, B. / Gambin, Y. / Sierecki, E. / Landsberg, M.J. / Stacey, K.J. / Egelman, E.H. / Kobe, B. | ||||||
Funding support | Australia, 1items
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Citation | Journal: Nat Struct Mol Biol / Year: 2017 Title: Structural basis of TIR-domain-assembly formation in MAL- and MyD88-dependent TLR4 signaling. Authors: Thomas Ve / Parimala R Vajjhala / Andrew Hedger / Tristan Croll / Frank DiMaio / Shane Horsefield / Xiong Yu / Peter Lavrencic / Zahid Hassan / Garry P Morgan / Ashley Mansell / Mehdi Mobli ...Authors: Thomas Ve / Parimala R Vajjhala / Andrew Hedger / Tristan Croll / Frank DiMaio / Shane Horsefield / Xiong Yu / Peter Lavrencic / Zahid Hassan / Garry P Morgan / Ashley Mansell / Mehdi Mobli / Ailis O'Carroll / Brieuc Chauvin / Yann Gambin / Emma Sierecki / Michael J Landsberg / Katryn J Stacey / Edward H Egelman / Bostjan Kobe / Abstract: Toll-like receptor (TLR) signaling is a key innate immunity response to pathogens. Recruitment of signaling adapters such as MAL (TIRAP) and MyD88 to the TLRs requires Toll/interleukin-1 receptor ...Toll-like receptor (TLR) signaling is a key innate immunity response to pathogens. Recruitment of signaling adapters such as MAL (TIRAP) and MyD88 to the TLRs requires Toll/interleukin-1 receptor (TIR)-domain interactions, which remain structurally elusive. Here we show that MAL TIR domains spontaneously and reversibly form filaments in vitro. They also form cofilaments with TLR4 TIR domains and induce formation of MyD88 assemblies. A 7-Å-resolution cryo-EM structure reveals a stable MAL protofilament consisting of two parallel strands of TIR-domain subunits in a BB-loop-mediated head-to-tail arrangement. Interface residues that are important for the interaction are conserved among different TIR domains. Although large filaments of TLR4, MAL or MyD88 are unlikely to form during cellular signaling, structure-guided mutagenesis, combined with in vivo interaction assays, demonstrated that the MAL interactions defined within the filament represent a template for a conserved mode of TIR-domain interaction involved in both TLR and interleukin-1 receptor signaling. | ||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 5uzb.cif.gz | 331.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb5uzb.ent.gz | 272.7 KB | Display | PDB format |
PDBx/mmJSON format | 5uzb.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 5uzb_validation.pdf.gz | 834.9 KB | Display | wwPDB validaton report |
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Full document | 5uzb_full_validation.pdf.gz | 852.3 KB | Display | |
Data in XML | 5uzb_validation.xml.gz | 52.5 KB | Display | |
Data in CIF | 5uzb_validation.cif.gz | 71.2 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/uz/5uzb ftp://data.pdbj.org/pub/pdb/validation_reports/uz/5uzb | HTTPS FTP |
-Related structure data
Related structure data | 8625MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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-Components
#1: Protein | Mass: 19689.162 Da / Num. of mol.: 14 / Fragment: UNP residues 79-221 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: TIRAP, MAL / Plasmid: pMCSG7 / Production host: Escherichia coli (E. coli) / References: UniProt: P58753 |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: FILAMENT / 3D reconstruction method: helical reconstruction |
-Sample preparation
Component | Name: MAL TIR domain filament / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Escherichia coli (E. coli) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD |
Specimen holder | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 20 e/Å2 / Film or detector model: FEI FALCON II (4k x 4k) / Num. of real images: 446 |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||
Helical symmerty | Angular rotation/subunit: -26.8 ° / Axial rise/subunit: 15.5 Å / Axial symmetry: C6 | ||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 7 Å / Resolution method: OTHER / Num. of particles: 17175 / Symmetry type: HELICAL |