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- EMDB-39424: Structure of the FADD/Caspase-8/cFLIP death effector domain assembly -

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Basic information

Entry
Database: EMDB / ID: EMD-39424
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 p10
    • 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 / death-inducing signaling complex assembly / negative regulation of activation-induced cell death of T cells / skeletal muscle atrophy / skeletal myofibril assembly / caspase-8 / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / death effector domain binding / tumor necrosis factor receptor superfamily binding / FasL/ CD95L signaling ...positive regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation / death-inducing signaling complex assembly / negative regulation of activation-induced cell death of T cells / skeletal muscle atrophy / skeletal myofibril assembly / caspase-8 / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / death effector domain binding / tumor necrosis factor receptor superfamily binding / FasL/ CD95L signaling / TRAIL signaling / regulation of skeletal muscle satellite cell proliferation / CD95 death-inducing signaling complex / Apoptotic execution phase / Activation, myristolyation of BID and translocation to mitochondria / Defective RIPK1-mediated regulated necrosis / Microbial modulation of RIPK1-mediated regulated necrosis / TRAIL-activated apoptotic signaling pathway / caspase binding / TRIF-mediated programmed cell death / ripoptosome / Regulation by c-FLIP / CASP8 activity is inhibited / Dimerization of procaspase-8 / positive regulation of extracellular matrix organization / TLR3-mediated TICAM1-dependent programmed cell death / positive regulation of hepatocyte proliferation / regulation of necroptotic process / negative regulation of hepatocyte apoptotic process / positive regulation of macrophage differentiation / self proteolysis / Caspase activation via Death Receptors in the presence of ligand / positive regulation of adaptive immune response / response to cobalt ion / positive regulation of glomerular mesangial cell proliferation / negative regulation of necroptotic process / skeletal muscle tissue regeneration / necroptotic signaling pathway / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / response to anesthetic / CLEC7A/inflammasome pathway / death-inducing signaling complex / spleen development / receptor serine/threonine kinase binding / positive regulation of type I interferon-mediated signaling pathway / positive regulation of innate immune response / natural killer cell activation / tumor necrosis factor receptor binding / death receptor binding / lymph node development / regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of activated T cell proliferation / positive regulation of extrinsic apoptotic signaling pathway / execution phase of apoptosis / negative regulation of cellular response to transforming growth factor beta stimulus / TNFR1-induced proapoptotic signaling / T cell homeostasis / RIPK1-mediated regulated necrosis / Apoptotic cleavage of cellular proteins / regulation of innate immune response / response to testosterone / extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of myoblast fusion / cellular response to dexamethasone stimulus / positive regulation of proteolysis / macrophage differentiation / negative regulation of cardiac muscle cell apoptotic process / skeletal muscle tissue development / B cell activation / response to tumor necrosis factor / pyroptotic inflammatory response / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / positive regulation of execution phase of apoptosis / Caspase-mediated cleavage of cytoskeletal proteins / extrinsic apoptotic signaling pathway / thymus development / negative regulation of reactive oxygen species biosynthetic process / kidney development / behavioral response to cocaine / cellular response to nitric oxide / cysteine-type peptidase activity / T cell differentiation in thymus / regulation of cytokine production / signaling adaptor activity / cellular response to epidermal growth factor stimulus / positive regulation of T cell mediated cytotoxicity / negative regulation of extrinsic apoptotic signaling pathway / apoptotic signaling pathway / : / negative regulation of canonical NF-kappaB signal transduction / positive regulation of interleukin-8 production / positive regulation of interleukin-1 beta production / T cell activation / cellular response to estradiol stimulus / protein maturation / Regulation of NF-kappa B signaling / positive regulation of neuron projection development / cellular response to mechanical stimulus / protein processing / Regulation of TNFR1 signaling
Similarity search - Function
FADD / : / Caspase-8 / Death effector domain / Death effector domain / Death effector domain (DED) profile. / Death effector domain / Death domain profile. / Peptidase family C14A, His active site / Caspase family histidine active site. ...FADD / : / Caspase-8 / Death effector domain / Death effector domain / Death effector domain (DED) profile. / Death effector domain / Death domain profile. / Peptidase family C14A, His active site / Caspase family histidine active site. / DEATH domain, found in proteins involved in cell death (apoptosis). / Death domain / Peptidase C14, caspase non-catalytic subunit p10 / Peptidase family C14A, cysteine active site / Death domain / 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: 3.66 Å
AuthorsLin S-C / Yang C-Y
Funding support Taiwan, 1 items
OrganizationGrant numberCountry
Other government Taiwan
CitationJournal: Nat Commun / Year: 2024
Title: Reverse hierarchical DED assembly in the cFLIP-procaspase-8 and cFLIP-procaspase-8-FADD complexes.
Authors: Chao-Yu Yang / Yi-Chun Tseng / Yi-Fan Tu / Bai-Jiun Kuo / Li-Chung Hsu / Chia-I Lien / You-Sheng Lin / Yin-Ting Wang / Yen-Chen Lu / Tsung-Wei Su / Yu-Chih Lo / Su-Chang Lin /
Abstract: cFLIP, a master anti-apoptotic regulator, targets the FADD-induced DED complexes of procaspase-8 in death receptor and ripoptosome signaling pathways. Several tumor cells maintain relatively high ...cFLIP, a master anti-apoptotic regulator, targets the FADD-induced DED complexes of procaspase-8 in death receptor and ripoptosome signaling pathways. Several tumor cells maintain relatively high levels of cFLIP in achieving their immortality. However, understanding the three-dimensional regulatory mechanism initiated or mediated by elevated levels of cFLIP has been limited by the absence of the atomic coordinates for cFLIP-induced DED complexes. Here we report the crystal plus cryo-EM structures to uncover an unconventional mechanism where cFLIP and procaspase-8 autonomously form a binary tandem DED complex, independent of FADD. This complex gains the ability to recruit FADD, thereby allosterically modulating cFLIP assembly and partially activating caspase-8 for RIPK1 cleavage. Our structure-guided mutagenesis experiments provide critical insights into these regulatory mechanisms, elucidating the resistance to apoptosis and necroptosis in achieving immortality. Finally, this research offers a unified model for the intricate bidirectional hierarchy-based processes using multiprotein helical assembly to govern cell fate decisions.
History
DepositionMar 11, 2024-
Header (metadata) releaseOct 30, 2024-
Map releaseOct 30, 2024-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_39424.png

Downloads & links

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Map

FileDownload / File: emd_39424.map.gz / Format: CCP4 / Size: 137.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 330 pix.
= 277.2 Å		0.84 Å/pix.
x 330 pix.
= 277.2 Å		0.84 Å/pix.
x 330 pix.
= 277.2 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.84 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-0.5956369 - 1.2725604
Average (Standard dev.)0.0015306827 (±0.0408895)
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_39424_half_map_1.map
Projections & Slices
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Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_39424_half_map_2.map
Projections & Slices
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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 p10
    • 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 (E. coli)
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: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 20.878479 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
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 / Details: FADD / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.29141 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MDPFLVLLHS VSSSLSSSEL TELKGLCLGR VGKRKLERVQ SGLDLFSMLL EQNDLEPGHT ELLRELLASL RRHDLLRRVD DFEAGAAAG AAPGEEDLCA AFNVICDNVG KDWRRLARQL KVSDTKIDSI EDRYPRNLTE RVRESLRIWK NTEKENATVA H LVGALRSC ...String:
MDPFLVLLHS VSSSLSSSEL TELKGLCLGR 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 chloride
20.0 mM(HOCH2)3CNH2Tris
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 279 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 72.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / 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
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 246000
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.66 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 24014
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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