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- PDB-9dk8: TRIF TIR Filament Cryo-EM Structure -

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Basic information

Entry
Database: PDB / ID: 9dk8
TitleTRIF TIR Filament Cryo-EM Structure
ComponentsTIR domain-containing adapter molecule 1
KeywordsIMMUNE SYSTEM / TRIF / TICAM 1 / TIR domain / innate 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)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsManik, M.K. / Xiao, L. / Wu, H.
Funding support United States, 1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 22, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
E: TIR domain-containing adapter molecule 1
B: TIR domain-containing adapter molecule 1
F: TIR domain-containing adapter molecule 1
D: TIR domain-containing adapter molecule 1
A: TIR domain-containing adapter molecule 1
C: TIR domain-containing adapter molecule 1


Theoretical massNumber of molelcules
Total (without water)351,1906
Polymers351,1906
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
TIR domain-containing adapter molecule 1 / TICAM-1 / Proline-rich / vinculin and TIR domain-containing protein B / Putative NF-kappa-B- ...TICAM-1 / Proline-rich / vinculin and TIR domain-containing protein B / Putative NF-kappa-B-activating protein 502H / Toll-interleukin-1 receptor domain-containing adapter protein inducing interferon beta / MyD88-3 / TIR domain-containing adapter protein inducing IFN-beta


Mass: 58531.676 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TICAM1, PRVTIRB, TRIF / Plasmid: pcDNA3 TEV-GFP-FLAG LIC cloning vector (6LD)
Details (production host): Modified LIC 6D backbone with a C-terminal TEV-GFP-FLAG tag. Derived from Scott Gradia's pcDNA3.1 LIC 6D by Liron David.
Production host: Mammalian expression vector Flag-MCS-pcDNA3.1 (others)
References: UniProt: Q8IUC6
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: TRIF TIR Filament Cryo-EM Structure / Type: CELL / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Mammalian expression vector Flag-MCS-pcDNA3.1 (others)
Buffer solutionpH: 8
Buffer component
IDConc.NameBuffer-ID
120 mMTris1
2150 mMNaCl1
31 mMTCEP1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: Quantifoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 61.157 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: 178 ° / Axial rise/subunit: 16 Å / Axial symmetry: C1
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 2027995 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0036810
ELECTRON MICROSCOPYf_angle_d0.5339222
ELECTRON MICROSCOPYf_dihedral_angle_d4.351912
ELECTRON MICROSCOPYf_chiral_restr0.0391056
ELECTRON MICROSCOPYf_plane_restr0.0041218

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