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- PDB-9u7a: FADD-DED filaments coordinate complex IIa assembly during TNF-ind... -

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Basic information

Entry
Database: PDB / ID: 9u7a
TitleFADD-DED filaments coordinate complex IIa assembly during TNF-induced apoptosis
ComponentsFAS-associated death domain protein
KeywordsIMMUNE SYSTEM / RNA recognition / RNA helicase / ATP hydrolysis / RLR signaling
Function / homology
Function and homology information


positive regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation / negative regulation of activation-induced cell death of T cells / death effector domain binding / tumor necrosis factor receptor superfamily binding / FasL/ CD95L signaling / TRAIL signaling / CD95 death-inducing signaling complex / death-inducing signaling complex assembly / ripoptosome / Defective RIPK1-mediated regulated necrosis ...positive regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation / negative regulation of activation-induced cell death of T cells / death effector domain binding / tumor necrosis factor receptor superfamily binding / FasL/ CD95L signaling / TRAIL signaling / CD95 death-inducing signaling complex / death-inducing signaling complex assembly / ripoptosome / Defective RIPK1-mediated regulated necrosis / TRAIL-activated apoptotic signaling pathway / caspase binding / TRIF-mediated programmed cell death / Regulation by c-FLIP / CASP8 activity is inhibited / Dimerization of procaspase-8 / TLR3-mediated TICAM1-dependent programmed cell death / positive regulation of adaptive immune response / Caspase activation via Death Receptors in the presence of ligand / positive regulation of macrophage differentiation / necroptotic signaling pathway / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / death-inducing signaling complex / receptor serine/threonine kinase binding / negative regulation of necroptotic process / positive regulation of type I interferon-mediated signaling pathway / tumor necrosis factor receptor binding / death receptor binding / positive regulation of innate immune response / positive regulation of extrinsic apoptotic signaling pathway / TNFR1-induced proapoptotic signaling / motor neuron apoptotic process / RIPK1-mediated regulated necrosis / positive regulation of activated T cell proliferation / T cell homeostasis / positive regulation of proteolysis / extrinsic apoptotic signaling pathway via death domain receptors / positive regulation of execution phase of apoptosis / lymph node development / behavioral response to cocaine / spleen development / extrinsic apoptotic signaling pathway / signaling adaptor activity / extrinsic apoptotic signaling pathway in absence of ligand / thymus development / Regulation of TNFR1 signaling / positive regulation of interleukin-8 production / apoptotic signaling pathway / kidney development / Regulation of necroptotic cell death / cellular response to mechanical stimulus / positive regulation of T cell mediated cytotoxicity / cytoplasmic side of plasma membrane / positive regulation of type II interferon production / positive regulation of tumor necrosis factor production / T cell differentiation in thymus / cell body / protease binding / protein-macromolecule adaptor activity / defense response to virus / positive regulation of canonical NF-kappaB signal transduction / positive regulation of apoptotic process / innate immune response / apoptotic process / protein-containing complex binding / positive regulation of transcription by RNA polymerase II / identical protein binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
FADD / : / Death effector domain / Death effector domain / Death effector domain (DED) profile. / Death effector domain / Death domain profile. / DEATH domain, found in proteins involved in cell death (apoptosis). / Death domain / Death domain / Death-like domain superfamily
Similarity search - Domain/homology
FAS-associated death domain protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.82 Å
AuthorsLiu, P. / Luo, D.
Funding support Singapore, 1items
OrganizationGrant numberCountry
National Research Foundation (NRF, Singapore)NRF-CRP26-2021-0001 Singapore
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: DED filaments coordinate complex IIa assembly during TNF-induced apoptosis.
Authors: Ying Chen / Vinh Thang Huynh / Lihua Lai / Ping Liu / Tongyang Li / Yaw Bia Tan / Che Shin Chew / Amhed Missael Vargas Velazquez / Firdaus Samsudin / Jan K Marzinek / Peter J Bond / Bin Wu / ...Authors: Ying Chen / Vinh Thang Huynh / Lihua Lai / Ping Liu / Tongyang Li / Yaw Bia Tan / Che Shin Chew / Amhed Missael Vargas Velazquez / Firdaus Samsudin / Jan K Marzinek / Peter J Bond / Bin Wu / Dahai Luo / Vinay Tergaonkar /
Abstract: Extrinsic apoptosis is initiated by signaling from death receptors, leading to the assembly of RIPK1, FADD, and caspase-8 complex. Subsequently, caspase-8 forms a filamentous structure through the ...Extrinsic apoptosis is initiated by signaling from death receptors, leading to the assembly of RIPK1, FADD, and caspase-8 complex. Subsequently, caspase-8 forms a filamentous structure through the oligomerization of its tandem death effector domain (tDED), resulting in caspase activation and cell death. Although the DED of FADD (DED) is homologous to the tDEDs of caspase-8 (tDED) and both oligomerize to function, the functional form of DED oligomer in extrinsic apoptosis remains unclear. Here, using cryogenic-electron microscopy, we elucidate the structure of DED filaments comprising three helical chains assembled through three types of iterative interactions. Mutations disrupting DED filament formation impair the recruitment of RIPK1 and caspase-8, and abrogate the cell death response, suggesting that DED filamentation represents an important mechanistic step in the initiation of TNF-induced extrinsic apoptosis. Contrary to the belief that the homotypic death domains of RIPK1 and FADD are solely responsible for their interaction, we here show this interaction requires DED filamentation. Furthermore, cFLIP can disrupt DED filaments, uncovering an additional antiapoptotic mechanism of cFLIP beyond its disruption of caspase-8 filament. Molecular dynamics simulations reveal that DED filament thermodynamically favors tDED monomer over DED monomer, thus explaining the hierarchy and stoichiometry of FADD/caspase-8 complex assembly. These findings highlight the hitherto unappreciated roles of DED filament formation in extrinsic apoptosis.
History
DepositionMar 24, 2025Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 20, 2025Provider: repository / Type: Initial release
Revision 1.0Aug 20, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Aug 20, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Aug 20, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Aug 20, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Aug 20, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Sep 3, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: FAS-associated death domain protein
C: FAS-associated death domain protein
D: FAS-associated death domain protein
E: FAS-associated death domain protein
F: FAS-associated death domain protein
G: FAS-associated death domain protein
H: FAS-associated death domain protein
I: FAS-associated death domain protein
J: FAS-associated death domain protein
K: FAS-associated death domain protein
L: FAS-associated death domain protein
M: FAS-associated death domain protein
N: FAS-associated death domain protein
O: FAS-associated death domain protein
P: FAS-associated death domain protein
Q: FAS-associated death domain protein
R: FAS-associated death domain protein
S: FAS-associated death domain protein
T: FAS-associated death domain protein
U: FAS-associated death domain protein
V: FAS-associated death domain protein
W: FAS-associated death domain protein
X: FAS-associated death domain protein
Y: FAS-associated death domain protein


Theoretical massNumber of molelcules
Total (without water)244,84124
Polymers244,84124
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 ...
FAS-associated death domain protein / FAS-associating death domain-containing protein / Growth-inhibiting gene 3 protein / Mediator of ...FAS-associating death domain-containing protein / Growth-inhibiting gene 3 protein / Mediator of receptor induced toxicity


Mass: 10201.722 Da / Num. of mol.: 24
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FADD, MORT1, GIG3 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q13158
Has protein modificationN

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Experimental details

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Experiment

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

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Sample preparation

Component
IDNameTypeDetailsEntity IDParent-IDSource
1FADD-DED filamentCOMPLEXFADD-DED filament formation during apoptosisall0RECOMBINANT
2FADD-filamentCOMPLEXFADD-filamentall1RECOMBINANT
Molecular weightValue: 0.42 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5 / Details: 25mM HEPES, 150mM NaCl
Buffer component
IDConc.NameFormulaBuffer-ID
125 mMHEPESHEPES1
2150 mMsodium chlorideNaCl1
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: The sample forms filament.
Specimen supportGrid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 283.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 400 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 6163

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Processing

EM software
IDNameVersionCategoryDetails
1Topazparticle selection
2cryoSPARCparticle selection
3EPUimage acquisition
5cryoSPARCCTF correction
8UCSF ChimeraXmodel fitting
10PHENIX1.20.1_4487:model refinement
11Cootmodel refinement
12cryoSPARCinitial Euler assignment
13cryoSPARCfinal Euler assignmenthelical refinement
14cryoSPARCclassificationheterogenous refinement
15cryoSPARC3D reconstructionhelical refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionDetails: topaz train/extract
3D reconstructionResolution: 2.82 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 90187 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingDetails: ModelAngelo / Source name: Other / Type: in silico model

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