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- EMDB-46946: TRIF TIR Filament Cryo-EM Structure -

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Basic information

Entry
Database: EMDB / ID: EMD-46946
TitleTRIF TIR Filament Cryo-EM Structure
Map dataCryo-EM structure of the human TRIF/ TICAM 1 TIR filament.
Sample
  • Cell: TRIF TIR Filament Cryo-EM Structure
    • Protein or peptide: TIR domain-containing adapter molecule 1
KeywordsTRIF / TICAM 1 / TIR domain / innate immune system / IMMUNE SYSTEM
Function / homology
Function and homology information


TICAM1 deficiency - HSE / TRAF3 deficiency - HSE / positive regulation of natural killer cell activation / ripoptosome / MyD88-independent TLR4 cascade / Toll Like Receptor 3 (TLR3) Cascade / TRIF-mediated programmed cell death / TLR3-mediated TICAM1-dependent programmed cell death / positive regulation of myeloid dendritic cell cytokine production / cellular response to oxidised low-density lipoprotein particle stimulus ...TICAM1 deficiency - HSE / TRAF3 deficiency - HSE / positive regulation of natural killer cell activation / ripoptosome / MyD88-independent TLR4 cascade / Toll Like Receptor 3 (TLR3) Cascade / TRIF-mediated programmed cell death / TLR3-mediated TICAM1-dependent programmed cell death / positive regulation of myeloid dendritic cell cytokine production / cellular response to oxidised low-density lipoprotein particle stimulus / Caspase activation via Death Receptors in the presence of ligand / toll-like receptor 3 signaling pathway / TRIF-dependent toll-like receptor signaling pathway / RIP-mediated NFkB activation via ZBP1 / macrophage activation involved in immune response / positive regulation of cytokine production involved in inflammatory response / positive regulation of macrophage cytokine production / toll-like receptor 4 signaling pathway / toll-like receptor signaling pathway / response to exogenous dsRNA / B cell proliferation / positive regulation of type I interferon production / regulation of protein-containing complex assembly / positive regulation of chemokine production / positive regulation of autophagy / signaling adaptor activity / positive regulation of B cell proliferation / nitric oxide biosynthetic process / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / TRAF6-mediated induction of TAK1 complex within TLR4 complex / autophagosome / positive regulation of interferon-beta production / lipopolysaccharide-mediated signaling pathway / TICAM1, RIP1-mediated IKK complex recruitment / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / IKK complex recruitment mediated by RIP1 / positive regulation of protein ubiquitination / apoptotic signaling pathway / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / positive regulation of nitric oxide biosynthetic process / cellular response to lipopolysaccharide / molecular adaptor activity / defense response to virus / positive regulation of canonical NF-kappaB signal transduction / early endosome / endosome / endosome membrane / inflammatory response / innate immune response / positive regulation of gene expression / protein kinase binding / mitochondrion / cytosol
Similarity search - Function
TIR domain-containing adapter molecule 1 / TRIF, N-terminal / TRIF N-terminal domain / : / RHIM domain / RIP homotypic interaction motif / 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 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsManik MK / Xiao L / Wu H
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
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 8, 2024-
Header (metadata) releaseJan 22, 2025-
Map releaseJan 22, 2025-
UpdateJan 22, 2025-
Current statusJan 22, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46946.png

Downloads & links

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Map

FileDownload / File: emd_46946.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of the human TRIF/ TICAM 1 TIR filament.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 211.2 Å		0.83 Å/pix.
x 256 pix.
= 211.2 Å		0.83 Å/pix.
x 256 pix.
= 211.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.44985703 - 0.8776707
Average (Standard dev.)0.002035276 (±0.024723927)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 211.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map B

Fileemd_46946_half_map_1.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map A

Fileemd_46946_half_map_2.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : TRIF TIR Filament Cryo-EM Structure

EntireName: TRIF TIR Filament Cryo-EM Structure
Components
  • Cell: TRIF TIR Filament Cryo-EM Structure
    • Protein or peptide: TIR domain-containing adapter molecule 1

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Supramolecule #1: TRIF TIR Filament Cryo-EM Structure

SupramoleculeName: TRIF TIR Filament Cryo-EM Structure / type: cell / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: TIR domain-containing adapter molecule 1

MacromoleculeName: TIR domain-containing adapter molecule 1 / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 58.531676 KDa
Recombinant expressionOrganism: Mammalian expression vector Flag-MCS-pcDNA3.1 (others)
SequenceString: MACTGPSLPS AFDILGAAGQ DKLLYLKHKL KTPRPGCQGQ DLLHAMVLLK LGQETEARIS LEALKADAVA RLVARQWAGV DSTEDPEEP PDVSWAVARL YHLLAEEKLC PASLRDVAYQ EAVRTLSSRD DHRLGELQDE ARNRCGWDIA GDPGSIRTLQ S NLGCLPPS ...String:
MACTGPSLPS AFDILGAAGQ DKLLYLKHKL KTPRPGCQGQ DLLHAMVLLK LGQETEARIS LEALKADAVA RLVARQWAGV DSTEDPEEP PDVSWAVARL YHLLAEEKLC PASLRDVAYQ EAVRTLSSRD DHRLGELQDE ARNRCGWDIA GDPGSIRTLQ S NLGCLPPS SALPSGTRSL PRPIDGVSDW SQGCSLRSTG SPASLASNLE ISQSPTMPFL SLHRSPHGPS KLCDDPQASL VP EPVPGGC QEPEEMSWPP SGEIASPPEL PSSPPPGLPE VAPDATSTGL PDTPAAPETS TNYPVECTEG SAGPQSLPLP ILE PVKNPC SVKDQTPLQL SVEDTTSPNT KPCPPTPTTP ETSPPPPPPP PSSTPCSAHL TPSSLFPSSL ESSSEQKFYN FVIL HARAD EHIALRVREK LEALGVPDGA TFCEDFQVPG RGELSCLQDA IDHSAFIILL LTSNFDCRLS LHQVNQAMMS NLTRQ GSPD CVIPFLPLES SPAQLSSDTA SLLSGLVRLD EHSQIFARKV ANTFKPHRLQ ARKAMWRKEQ D

UniProtKB: TIR domain-containing adapter molecule 1

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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: 8
Component:
ConcentrationName
20.0 mMTris
150.0 mMNaCl
1.0 mMTCEP
GridModel: Quantifoil / Material: GOLD / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 61.157 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 16.0 Å
Applied symmetry - Helical parameters - Δ&Phi: 178 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 2027995
Startup modelType of model: OTHER
Details: Alphafold model of the TIR domain was used as the initial model.
Final angle assignmentType: NOT APPLICABLE

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