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- EMDB-8625: Cryo-EM structure of the MAL TIR domain filament -

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Basic information

Entry
Database: EMDB / ID: EMD-8625
TitleCryo-EM structure of the MAL TIR domain filament
Map dataCryo-EM structure of the MAL TIR domain filament
Sample
  • Complex: MAL TIR domain filament
    • Protein or peptide: Toll/interleukin-1 receptor domain-containing adapter protein
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 / MyD88 deficiency (TLR2/4) / positive regulation of neutrophil chemotaxis / MyD88-dependent toll-like receptor signaling pathway / IRAK4 deficiency (TLR2/4) / regulation of innate immune response / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / toll-like receptor 4 signaling pathway / 3'-UTR-mediated mRNA stabilization / regulation of stress-activated MAPK cascade / cellular response to lipoteichoic acid / endocytic vesicle / canonical NF-kappaB signal transduction / signaling adaptor activity / positive regulation of B cell proliferation / phosphatidylinositol-4,5-bisphosphate binding / extrinsic component of cytoplasmic side of plasma membrane / positive regulation of interleukin-12 production / protein kinase C binding / positive regulation of interleukin-8 production / positive regulation of protein-containing complex assembly / positive regulation of JNK cascade / ruffle membrane / positive regulation of interleukin-6 production / protein-macromolecule adaptor activity / positive regulation of tumor necrosis factor production / positive regulation of NF-kappaB transcription factor activity / ER-Phagosome pathway / positive regulation of canonical NF-kappaB signal transduction / 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 / cytosol / cytoplasm
Similarity search - Function
Toll-interleukin 1 receptor domain-containing adaptor protein, Tirap / TIR domain / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily
Similarity search - Domain/homology
Toll/interleukin-1 receptor domain-containing adapter protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 7.0 Å
AuthorsVe T / Vajjhala PR / Hedger A / Croll T / DiMaio F / Horsefield S / Yu X / Lavrencic P / Hassan Z / Morgan GP ...Ve T / Vajjhala PR / Hedger A / Croll T / DiMaio F / Horsefield S / Yu X / Lavrencic P / Hassan Z / Morgan GP / Mansell A / Mobli M / O'Carrol A / Chauvin B / Gambin Y / Sierecki E / Landsberg MJ / Stacey KJ / Egelman EH / Kobe B
Funding support Australia, 1 items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)1107804 Australia
CitationJournal: 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
DepositionFeb 25, 2017-
Header (metadata) releaseJul 26, 2017-
Map releaseJul 26, 2017-
UpdateJan 15, 2020-
Current statusJan 15, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 350
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 350
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-5uzb
  • Surface level: 350
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-5uzb
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_8625.png

Downloads & links

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Map

FileDownload / File: emd_8625.map.gz / Format: CCP4 / Size: 25.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of the MAL TIR domain filament
Voxel sizeX=Y=Z: 1.07 Å
Density
Contour LevelBy AUTHOR: 350 / Movie #1: 350
Minimum - Maximum-211.08592 - 781.7997
Average (Standard dev.)102.514694 (±152.01855)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-130-130-49
Dimensions260260100
Spacing260260100
CellA: 278.2 Å / B: 278.2 Å / C: 107.00001 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.071.071.07
M x/y/z260260100
origin x/y/z0.0000.0000.000
length x/y/z278.200278.200107.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS-130-130-49
NC/NR/NS260260100
D min/max/mean-211.086781.800102.515

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Supplemental data

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Sample components

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Entire : MAL TIR domain filament

EntireName: MAL TIR domain filament
Components
  • Complex: MAL TIR domain filament
    • Protein or peptide: Toll/interleukin-1 receptor domain-containing adapter protein

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Supramolecule #1: MAL TIR domain filament

SupramoleculeName: MAL TIR domain filament / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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Macromolecule #1: Toll/interleukin-1 receptor domain-containing adapter protein

MacromoleculeName: Toll/interleukin-1 receptor domain-containing adapter protein
type: protein_or_peptide / ID: 1 / Number of copies: 14 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 19.689162 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MHHHHHHSSG VDLGTENLYF QSNAEQKLIS EEDLSSRWSK DYDVCVCHSE EDLVAAQDLV SYLEGSTASL RCFLQLRDAT PGGAIVSEL CQALSSSHCR VLLITPGFLQ DPWCKYQMLQ ALTEAPGAEG CTIPLLSGLS RAAYPPELRF MYYVDGRGPD G GFRQVKEA VMRYLQTLS

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingFilm or detector model: FEI FALCON II (4k x 4k) / Number real images: 446 / Average electron dose: 20.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: CTFFIND3
Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Helical parameters - Δz: 15.5 Å
Applied symmetry - Helical parameters - Δ&Phi: -26.8 °
Applied symmetry - Helical parameters - Axial symmetry: C6 (6 fold cyclic)
Resolution.type: BY AUTHOR / Resolution: 7.0 Å / Resolution method: OTHER / Software: (Name: SPIDER, IHRSR) / Number images used: 17175

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