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- EMDB-39126: Structure of the FADD/Caspase-8/cFLIP death effector domain assembly -

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Basic information

Entry
Database: EMDB / ID: EMD-39126
TitleStructure of the FADD/Caspase-8/cFLIP death effector domain assembly
Map datasharpened map
Sample
  • Complex: FADD/Caspase-8/cFLIP death effector domain assembly
    • Protein or peptide: Caspase-8 subunit p10Caspase 8
    • Protein or peptide: CASP8 and FADD-like apoptosis regulator subunit p43
    • Protein or peptide: FAS-associated death domain protein
KeywordsFADD / caspase-8 / cellular FLICE-like inhibitory protein / Death effector domain / APOPTOSIS
Function / homology
Function and homology information


positive regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation / negative regulation of myoblast fusion / negative regulation of activation-induced cell death of T cells / skeletal myofibril assembly / caspase-8 / death effector domain binding / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / FasL/ CD95L signaling / skeletal muscle atrophy / TRAIL signaling ...positive regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation / negative regulation of myoblast fusion / negative regulation of activation-induced cell death of T cells / skeletal myofibril assembly / caspase-8 / death effector domain binding / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / FasL/ CD95L signaling / skeletal muscle atrophy / TRAIL signaling / CD95 death-inducing signaling complex / regulation of skeletal muscle satellite cell proliferation / tumor necrosis factor receptor superfamily binding / death-inducing signaling complex assembly / ripoptosome / Defective RIPK1-mediated regulated necrosis / Apoptotic execution phase / Activation, myristolyation of BID and translocation to mitochondria / TRAIL-activated apoptotic signaling pathway / TRIF-mediated programmed cell death / TLR3-mediated TICAM1-dependent programmed cell death / Microbial modulation of RIPK1-mediated regulated necrosis / Regulation by c-FLIP / CASP8 activity is inhibited / Dimerization of procaspase-8 / regulation of necroptotic process / positive regulation of adaptive immune response / Caspase activation via Death Receptors in the presence of ligand / skeletal muscle tissue regeneration / positive regulation of extracellular matrix organization / positive regulation of glomerular mesangial cell proliferation / positive regulation of macrophage differentiation / caspase binding / necroptotic signaling pathway / self proteolysis / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / response to cobalt ion / cysteine-type endopeptidase activity involved in apoptotic signaling pathway / death-inducing signaling complex / negative regulation of hepatocyte apoptotic process / negative regulation of necroptotic process / natural killer cell activation / CLEC7A/inflammasome pathway / receptor serine/threonine kinase binding / regulation of tumor necrosis factor-mediated signaling pathway / activation of cysteine-type endopeptidase activity / positive regulation of innate immune response / positive regulation of type I interferon-mediated signaling pathway / tumor necrosis factor receptor binding / death receptor binding / positive regulation of hepatocyte proliferation / positive regulation of extrinsic apoptotic signaling pathway / cysteine-type endopeptidase activity involved in apoptotic process / negative regulation of cellular response to transforming growth factor beta stimulus / motor neuron apoptotic process / TNFR1-induced proapoptotic signaling / negative regulation of cardiac muscle cell apoptotic process / execution phase of apoptosis / RIPK1-mediated regulated necrosis / positive regulation of execution phase of apoptosis / response to testosterone / B cell activation / regulation of innate immune response / positive regulation of activated T cell proliferation / pyroptotic inflammatory response / Apoptotic cleavage of cellular proteins / T cell homeostasis / behavioral response to cocaine / positive regulation of proteolysis / macrophage differentiation / protein maturation / cellular response to organic cyclic compound / enzyme activator activity / extrinsic apoptotic signaling pathway via death domain receptors / cellular response to nitric oxide / Caspase-mediated cleavage of cytoskeletal proteins / lymph node development / response to tumor necrosis factor / signaling adaptor activity / negative regulation of canonical NF-kappaB signal transduction / skeletal muscle tissue development / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / extrinsic apoptotic signaling pathway / negative regulation of reactive oxygen species biosynthetic process / keratinocyte differentiation / regulation of cytokine production / extrinsic apoptotic signaling pathway in absence of ligand / cellular response to epidermal growth factor stimulus / cysteine-type peptidase activity / spleen development / cellular response to dexamethasone stimulus / T cell activation / proteolysis involved in protein catabolic process / erythrocyte differentiation / thymus development / kidney development / positive regulation of interleukin-1 beta production / Regulation of NF-kappa B signaling / cellular response to estradiol stimulus / positive regulation of interleukin-8 production
Similarity search - Function
: / FADD / Caspase-8 / 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 ...: / FADD / Caspase-8 / 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 / Peptidase family C14A, His active site / Caspase family histidine active site. / Peptidase C14, caspase non-catalytic subunit p10 / Peptidase family C14A, cysteine active site / Caspase family cysteine active site. / Caspase family p10 domain profile. / Peptidase C14A, caspase catalytic domain / Caspase, interleukin-1 beta converting enzyme (ICE) homologues / Peptidase C14, p20 domain / Caspase family p20 domain profile. / : / Caspase domain / Caspase-like domain superfamily / Death-like domain superfamily
Similarity search - Domain/homology
CASP8 and FADD-like apoptosis regulator / FAS-associated death domain protein / Caspase-8
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.68 Å
AuthorsLin S-C / Yang C-Y
Funding support Taiwan, 1 items
OrganizationGrant numberCountry
Other government Taiwan
CitationJournal: Nat Commun / Year: 2024
Title: Deciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis.
Authors: Chao-Yu Yang / Chia-I Lien / Yi-Chun Tseng / Yi-Fan Tu / Arkadiusz W Kulczyk / Yen-Chen Lu / Yin-Ting Wang / Tsung-Wei Su / Li-Chung Hsu / Yu-Chih Lo / Su-Chang Lin /
Abstract: Fas-associated protein with death domain (FADD), procaspase-8, and cellular FLICE-inhibitory proteins (cFLIP) assemble through death-effector domains (DEDs), directing death receptor signaling ...Fas-associated protein with death domain (FADD), procaspase-8, and cellular FLICE-inhibitory proteins (cFLIP) assemble through death-effector domains (DEDs), directing death receptor signaling towards cell survival or apoptosis. Understanding their three-dimensional regulatory mechanism has been limited by the absence of atomic coordinates for their ternary DED complex. By employing X-ray crystallography and cryogenic electron microscopy (cryo-EM), we present the atomic coordinates of human FADD-procaspase-8-cFLIP complexes, revealing structural insights into these critical interactions. These structures illustrate how FADD and cFLIP orchestrate the assembly of caspase-8-containing complexes and offer mechanistic explanations for their role in promoting or inhibiting apoptotic and necroptotic signaling. A helical procaspase-8-cFLIP hetero-double layer in the complex appears to promote limited caspase-8 activation for cell survival. Our structure-guided mutagenesis supports the role of the triple-FADD complex in caspase-8 activation and in regulating receptor-interacting protein kinase 1 (RIPK1). These results propose a unified mechanism for DED assembly and procaspase-8 activation in the regulation of apoptotic and necroptotic signaling across various cellular pathways involved in development, innate immunity, and disease.
History
DepositionFeb 16, 2024-
Header (metadata) releaseMay 15, 2024-
Map releaseMay 15, 2024-
UpdateMay 15, 2024-
Current statusMay 15, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_39126.png

Downloads & links

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Map

FileDownload / File: emd_39126.map.gz / Format: CCP4 / Size: 137.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Voxel sizeX=Y=Z: 0.84 Å
Density
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.28484416 - 0.46650007
Average (Standard dev.)0.00032665388 (±0.012925275)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions330330330
Spacing330330330
CellA=B=C: 277.19998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_39126_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_39126_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : FADD/Caspase-8/cFLIP death effector domain assembly

EntireName: FADD/Caspase-8/cFLIP death effector domain assembly
Components
  • Complex: FADD/Caspase-8/cFLIP death effector domain assembly
    • Protein or peptide: Caspase-8 subunit p10Caspase 8
    • Protein or peptide: CASP8 and FADD-like apoptosis regulator subunit p43
    • Protein or peptide: FAS-associated death domain protein

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Supramolecule #1: FADD/Caspase-8/cFLIP death effector domain assembly

SupramoleculeName: FADD/Caspase-8/cFLIP death effector domain assembly / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Caspase-8 subunit p10

MacromoleculeName: Caspase-8 subunit p10 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.191648 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString: MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS FLKELLFRIN RLDLLITYLN TRKEEMERE LQTPGRAQIS AYRVMLYQIS EEVSRSELRS FKGGLQEEIS KCKLDDDMNL LDIFIEMEKR VILGEGKLDI L KRVCAQIN ...String:
MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS FLKELLFRIN RLDLLITYLN TRKEEMERE LQTPGRAQIS AYRVMLYQIS EEVSRSELRS FKGGLQEEIS KCKLDDDMNL LDIFIEMEKR VILGEGKLDI L KRVCAQIN KSLLKIINDY EEFSKERSSS LEGSPDEFSN GEELCGVMTI SDSPREQDSE SQTLDKVYQM KSKPRGYCLI IN NHNFAKA REKVPKLHSI RDRNGTHLDA GALTTTFEEL HFEIKPHDDC TVEQIYEILK IYQLMDHSNM DCFICCILSH GDK GIIYGT DGQEAPIYEL TSQFTGLKCP SLAGKPKVFF IQAAQGDNYQ KGIPVETASE EQPYLEMALS SPQTRYIPDE ADFL LGMAT VNNCVSYRNP AEGTWYIQSL CQSLRERCPR GDDILTILTE VNYEVSNKDD KKNMGKQMPQ PTFTLRKKLV FPSD

UniProtKB: Caspase-8

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Macromolecule #2: CASP8 and FADD-like apoptosis regulator subunit p43

MacromoleculeName: CASP8 and FADD-like apoptosis regulator subunit p43 / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 20.878479 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString:
MSAEVIHQVE EALDTDEKEM LLFLCRDVAI DVVPPNVRDL LDILRERGKL SVGDLAELLY RVRRFDLLKR ILKMDRKAVE THLLRNPHL VSDYRVLMAE IGEDLDKSDV SSLIFLMKDY MGRGKISKEK SFLDLVVELE KLNLVAPDQL DLLEKCLKNI H RIDLKTKI QKYKQSVQGA GTS

UniProtKB: CASP8 and FADD-like apoptosis regulator

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Macromolecule #3: FAS-associated death domain protein

MacromoleculeName: FAS-associated death domain protein / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.381533 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString: MDPFLVLLHS VSSSLSSSEL TELKFLCLGR VGKRKLERVQ SGLDLFSMLL EQNDLEPGHT ELLRELLASL RRHDLLRRVD DFEAGAAAG AAPGEEDLCA AFNVICDNVG KDWRRLARQL KVSDTKIDSI EDRYPRNLTE RVRESLRIWK NTEKENATVA H LVGALRSC ...String:
MDPFLVLLHS VSSSLSSSEL TELKFLCLGR VGKRKLERVQ SGLDLFSMLL EQNDLEPGHT ELLRELLASL RRHDLLRRVD DFEAGAAAG AAPGEEDLCA AFNVICDNVG KDWRRLARQL KVSDTKIDSI EDRYPRNLTE RVRESLRIWK NTEKENATVA H LVGALRSC QMNLVADLVQ EVQQARDLQN RSGAMSPMSW NSDASTSEAS LEHHHHHH

UniProtKB: FAS-associated death domain protein

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.2 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
80.0 mMNaClSodium chloridesodium chloride
20.0 mM(HOCH2)3CNH2Tris
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 279 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 165000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 72.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 356000
Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.68 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 28685
FSC plot (resolution estimation)

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