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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-8625 | |||||||||
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Title | Cryo-EM structure of the MAL TIR domain filament | |||||||||
![]() | Cryo-EM structure of the MAL TIR domain filament | |||||||||
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Function / homology | ![]() 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) / 3'-UTR-mediated mRNA stabilization / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / toll-like receptor 4 signaling pathway / regulation of stress-activated MAPK cascade / regulation of innate immune response / cellular response to lipoteichoic acid / endocytic vesicle / canonical NF-kappaB signal transduction / signaling adaptor activity / positive regulation of B cell proliferation / extrinsic component of cytoplasmic side of plasma membrane / 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 / positive regulation of protein-containing complex assembly / ruffle membrane / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / protein-macromolecule adaptor activity / positive regulation of NF-kappaB transcription factor activity / ER-Phagosome pathway / positive regulation of canonical NF-kappaB signal transduction / response to lipopolysaccharide / molecular adaptor activity / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade / 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 | ![]() | |||||||||
Method | helical reconstruction / cryo EM / Resolution: 7.0 Å | |||||||||
![]() | Ve 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 | ![]()
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![]() | ![]() 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 |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 5.9 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 11.4 KB 11.4 KB | Display Display | ![]() |
Images | ![]() | 77.8 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 368.4 KB | Display | ![]() |
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Full document | ![]() | 367.9 KB | Display | |
Data in XML | ![]() | 5.1 KB | Display | |
Data in CIF | ![]() | 5.6 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 5uzbMC M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Cryo-EM structure of the MAL TIR domain filament | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. generated in cubic-lattice coordinate | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.07 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
-Entire : MAL TIR domain filament
Entire | Name: MAL TIR domain filament |
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Components |
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-Supramolecule #1: MAL TIR domain filament
Supramolecule | Name: MAL TIR domain filament / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() ![]() |
-Macromolecule #1: Toll/interleukin-1 receptor domain-containing adapter protein
Macromolecule | Name: Toll/interleukin-1 receptor domain-containing adapter protein type: protein_or_peptide / ID: 1 / Number of copies: 14 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 19.689162 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MHHHHHHSSG VDLGTENLYF QSNAEQKLIS EEDLSSRWSK DYDVCVCHSE EDLVAAQDLV SYLEGSTASL RCFLQLRDAT PGGAIVSEL CQALSSSHCR VLLITPGFLQ DPWCKYQMLQ ALTEAPGAEG CTIPLLSGLS RAAYPPELRF MYYVDGRGPD G GFRQVKEA VMRYLQTLS |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | helical reconstruction |
Aggregation state | filament |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: FEI FALCON II (4k x 4k) / Number real images: 446 / Average electron dose: 20.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Final reconstruction | Applied 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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CTF correction | Software - Name: CTFFIND3 |
Final angle assignment | Type: NOT APPLICABLE |