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- EMDB-46977: CryoEM structure of the TIR domain from human TRAM -

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Basic information

Entry
Database: EMDB / ID: EMD-46977
TitleCryoEM structure of the TIR domain from human TRAM
Map data
Sample
  • Complex: Self-assembly of TIR domain of TRIF-related adaptor protein (TRAM)
    • Protein or peptide: TIR domain-containing adapter molecule 2
KeywordsToll-like receptor / TIR / TRAM / IMMUNE SYSTEM
Function / homology
Function and homology information


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 / positive regulation of chemokine (C-C motif) ligand 5 production / positive regulation of toll-like receptor 4 signaling pathway / TRIF-mediated programmed cell death / 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 / positive regulation of chemokine (C-C motif) ligand 5 production / positive regulation of toll-like receptor 4 signaling pathway / TRIF-mediated programmed cell death / 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 / phagocytic cup / signaling adaptor activity / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / TRAF6-mediated induction of TAK1 complex within TLR4 complex / secretory granule membrane / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / IKK complex recruitment mediated by RIP1 / 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 / endosome membrane / inflammatory response / innate immune response / Neutrophil degranulation / endoplasmic reticulum / Golgi apparatus / plasma membrane
Similarity search - Function
: / TIR domain / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily
Similarity search - Domain/homology
TIR domain-containing adapter molecule 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 5.6 Å
AuthorsHedger A / Pospich S / Pan M / Gu W / Ve T / Raunser S / Landsberg M / Nanson JD / Kobe B
Funding support Australia, 5 items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)2025931 Australia
National Health and Medical Research Council (NHMRC, Australia)1196590 Australia
Australian Research Council (ARC)FL180100109 Australia
Australian Research Council (ARC)FT200100572 Australia
Australian Research Council (ARC)DE170100783 Australia
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
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
DepositionSep 11, 2024-
Header (metadata) releaseJan 22, 2025-
Map releaseJan 22, 2025-
UpdateJan 29, 2025-
Current statusJan 29, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46977.png

Downloads & links

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Map

FileDownload / File: emd_46977.map.gz / Format: CCP4 / Size: 18.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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AxesZ (Sec.)Y (Row.)X (Col.)
1.7 Å/pix.
x 168 pix.
= 285.6 Å		1.7 Å/pix.
x 168 pix.
= 285.6 Å		1.7 Å/pix.
x 168 pix.
= 285.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.7 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0315
Minimum - Maximum-0.065494865 - 0.12202817
Average (Standard dev.)0.00075199624 (±0.0055820937)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions168168168
Spacing168168168
CellA=B=C: 285.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_46977_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_46977_half_map_2.map
Projections & Slices
AxesZYX

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Histogram (log scale)

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Sample components

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Entire : Self-assembly of TIR domain of TRIF-related adaptor protein (TRAM)

EntireName: Self-assembly of TIR domain of TRIF-related adaptor protein (TRAM)
Components
  • Complex: Self-assembly of TIR domain of TRIF-related adaptor protein (TRAM)
    • Protein or peptide: TIR domain-containing adapter molecule 2

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Supramolecule #1: Self-assembly of TIR domain of TRIF-related adaptor protein (TRAM)

SupramoleculeName: Self-assembly of TIR domain of TRIF-related adaptor protein (TRAM)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: TIR domain-containing adapter molecule 2

MacromoleculeName: TIR domain-containing adapter molecule 2 / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.350752 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
EVFLKFVILH AEDDTDEALR VQNLLQDDFG IKPGIIFAEM PCGRQHLQNL DDAVNGSAWT ILLLTENFLR DTWCNFQFYT SLMNSVNRQ HKYNSVIPMR PLNNPLPRER TPFALQTINA LEEESRGFPT QVERIFQESV YKTQQTIWKE TRNMVQR

UniProtKB: TIR domain-containing adapter molecule 2

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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

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination 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 reconstructionApplied 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
Startup modelType of model: OTHER
Final angle assignmentType: NOT APPLICABLE

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