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Open data
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Basic information
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Title | CryoEM structure of the TIR domain from human TRAM | ||||||||||||||||||
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![]() | Toll-like receptor / TIR / TRAM / IMMUNE SYSTEM | ||||||||||||||||||
Function / homology | ![]() TRAM-dependent toll-like receptor 4 signaling pathway / positive regulation of interleukin-18-mediated signaling pathway / negative regulation of chemokine (C-C motif) ligand 5 production / MyD88-independent TLR4 cascade / negative regulation of toll-like receptor 4 signaling pathway / TRIF-mediated programmed cell death / positive regulation of chemokine (C-C motif) ligand 5 production / positive regulation of toll-like receptor 4 signaling pathway / Toll Like Receptor 4 (TLR4) Cascade / Caspase activation via Death Receptors in the presence of ligand ...TRAM-dependent toll-like receptor 4 signaling pathway / positive regulation of interleukin-18-mediated signaling pathway / negative regulation of chemokine (C-C motif) ligand 5 production / MyD88-independent TLR4 cascade / negative regulation of toll-like receptor 4 signaling pathway / TRIF-mediated programmed cell death / positive regulation of chemokine (C-C motif) ligand 5 production / positive regulation of toll-like receptor 4 signaling pathway / Toll Like Receptor 4 (TLR4) Cascade / Caspase activation via Death Receptors in the presence of ligand / TRIF-dependent toll-like receptor signaling pathway / toll-like receptor 4 signaling pathway / positive regulation of type I interferon production / phagocytosis / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / phagocytic cup / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / signaling adaptor activity / IKK complex recruitment mediated by RIP1 / secretory granule membrane / cell projection / late endosome membrane / late endosome / cellular response to lipopolysaccharide / early endosome membrane / molecular adaptor activity / early endosome / positive regulation of canonical NF-kappaB signal transduction / endosome membrane / endosome / inflammatory response / innate immune response / Neutrophil degranulation / endoplasmic reticulum / Golgi apparatus / plasma membrane Similarity search - Function | ||||||||||||||||||
Biological species | ![]() | ||||||||||||||||||
Method | helical reconstruction / cryo EM / Resolution: 5.6 Å | ||||||||||||||||||
![]() | Hedger A / Pospich S / Pan M / Gu W / Ve T / Raunser S / Landsberg M / Nanson JD / Kobe B | ||||||||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Structural basis for TIR domain-mediated innate immune signaling by Toll-like receptor adaptors TRIF and TRAM. Authors: Mohammad K Manik / Mengqi Pan / Le Xiao / Weixi Gu / Hyoyoung Kim / Sabrina Pospich / Andrew Hedger / Parimala R Vajjhala / Morris Y L Lee / Xiaoqi Qian / Michael J Landsberg / Thomas Ve / ...Authors: Mohammad K Manik / Mengqi Pan / Le Xiao / Weixi Gu / Hyoyoung Kim / Sabrina Pospich / Andrew Hedger / Parimala R Vajjhala / Morris Y L Lee / Xiaoqi Qian / Michael J Landsberg / Thomas Ve / Jeffrey D Nanson / Stefan Raunser / Katryn J Stacey / Hao Wu / Bostjan Kobe / ![]() ![]() ![]() Abstract: Innate immunity relies on Toll-like receptors (TLRs) to detect pathogen-associated molecular patterns. The TIR (Toll/interleukin-1 receptor) domain-containing TLR adaptors TRIF (TIR domain-containing ...Innate immunity relies on Toll-like receptors (TLRs) to detect pathogen-associated molecular patterns. The TIR (Toll/interleukin-1 receptor) domain-containing TLR adaptors TRIF (TIR domain-containing adaptor-inducing interferon-β) and TRAM (TRIF-related adaptor molecule) are essential for MyD88-independent TLR signaling. However, the structural basis of TRIF and TRAM TIR domain-based signaling remains unclear. Here, we present cryo-EM structures of filaments formed by TRIF and TRAM TIR domains at resolutions of 3.3 Å and 5.6 Å, respectively. Both structures reveal two-stranded parallel helical arrangements. Functional studies underscore the importance of intrastrand interactions, mediated by the BB-loop, and interstrand interactions in TLR4-mediated signaling. We also report the crystal structure of the monomeric TRAM TIR domain bearing the BB loop mutation C117H, which reveals conformational differences consistent with its inactivity. Our findings suggest a unified signaling mechanism by the TIR domains of the four signaling TLR adaptors MyD88, MAL, TRIF, and TRAM and reveal potential therapeutic targets for immunity-related disorders. | ||||||||||||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 1.6 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 15.1 KB 15.1 KB | Display Display | ![]() |
Images | ![]() | 44.8 KB | ||
Filedesc metadata | ![]() | 5.8 KB | ||
Others | ![]() ![]() | 8.5 MB 8.5 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 556 KB | Display | ![]() |
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Full document | ![]() | 555.5 KB | Display | |
Data in XML | ![]() | 9.7 KB | Display | |
Data in CIF | ![]() | 11.4 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 9dlgMC ![]() 9dk8C ![]() 9dkiC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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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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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.7 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_46977_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_46977_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Self-assembly of TIR domain of TRIF-related adaptor protein (TRAM)
Entire | Name: Self-assembly of TIR domain of TRIF-related adaptor protein (TRAM) |
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Components |
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-Supramolecule #1: Self-assembly of TIR domain of TRIF-related adaptor protein (TRAM)
Supramolecule | Name: Self-assembly of TIR domain of TRIF-related adaptor protein (TRAM) type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: TIR domain-containing adapter molecule 2
Macromolecule | Name: TIR domain-containing adapter molecule 2 / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 18.350752 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: EVFLKFVILH AEDDTDEALR VQNLLQDDFG IKPGIIFAEM PCGRQHLQNL DDAVNGSAWT ILLLTENFLR DTWCNFQFYT SLMNSVNRQ HKYNSVIPMR PLNNPLPRER TPFALQTINA LEEESRGFPT QVERIFQESV YKTQQTIWKE TRNMVQR UniProtKB: TIR domain-containing adapter molecule 2 |
-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 |
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Electron microscopy
Microscope | FEI TALOS ARCTICA |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 40.0 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 50.0 µm / Nominal defocus min: 3.0 µm |
Experimental equipment | ![]() Model: Talos Arctica / Image courtesy: FEI Company |
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Image processing
Final reconstruction | Applied symmetry - Helical parameters - Δz: 16.11 Å Applied symmetry - Helical parameters - Δ&Phi: 177.9 ° Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric) Resolution.type: BY AUTHOR / Resolution: 5.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 95000 |
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Startup model | Type of model: OTHER |
Final angle assignment | Type: NOT APPLICABLE |