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- EMDB-39428: Structure of the Caspase-8/cFLIP death effector domain assembly -

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Basic information

Entry
Database: EMDB / ID: EMD-39428
TitleStructure of the Caspase-8/cFLIP death effector domain assembly
Map datasharpened map
Sample
  • Complex: 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
KeywordsFADD / caspase-8 / cellular FLICE-like inhibitory protein / Death effector domain / APOPTOSIS
Function / homology
Function and homology information


negative regulation of myoblast fusion / skeletal myofibril assembly / caspase-8 / death effector domain binding / FasL/ CD95L signaling / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / skeletal muscle atrophy / TRAIL signaling / CD95 death-inducing signaling complex / regulation of skeletal muscle satellite cell proliferation ...negative regulation of myoblast fusion / skeletal myofibril assembly / caspase-8 / death effector domain binding / FasL/ CD95L signaling / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / skeletal muscle atrophy / TRAIL signaling / CD95 death-inducing signaling complex / regulation of skeletal muscle satellite cell proliferation / ripoptosome / Defective RIPK1-mediated regulated necrosis / TRAIL-activated apoptotic signaling pathway / Apoptotic execution phase / Activation, myristolyation of BID and translocation to mitochondria / TRIF-mediated programmed cell death / Microbial modulation of RIPK1-mediated regulated necrosis / Regulation by c-FLIP / CASP8 activity is inhibited / Dimerization of procaspase-8 / TLR3-mediated TICAM1-dependent programmed cell death / regulation of necroptotic process / Caspase activation via Death Receptors in the presence of ligand / positive regulation of extracellular matrix organization / positive regulation of macrophage differentiation / self proteolysis / positive regulation of glomerular mesangial cell proliferation / response to cobalt ion / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / death-inducing signaling complex / skeletal muscle tissue regeneration / CLEC7A/inflammasome pathway / negative regulation of necroptotic process / response to anesthetic / negative regulation of hepatocyte apoptotic process / regulation of tumor necrosis factor-mediated signaling pathway / tumor necrosis factor receptor binding / death receptor binding / positive regulation of hepatocyte proliferation / natural killer cell activation / negative regulation of cellular response to transforming growth factor beta stimulus / TNFR1-induced proapoptotic signaling / RIPK1-mediated regulated necrosis / negative regulation of cardiac muscle cell apoptotic process / execution phase of apoptosis / regulation of innate immune response / Apoptotic cleavage of cellular proteins / pyroptotic inflammatory response / response to testosterone / : / B cell activation / positive regulation of proteolysis / macrophage differentiation / response to tumor necrosis factor / extrinsic apoptotic signaling pathway via death domain receptors / Caspase-mediated cleavage of cytoskeletal proteins / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / skeletal muscle tissue development / negative regulation of reactive oxygen species biosynthetic process / extrinsic apoptotic signaling pathway / negative regulation of canonical NF-kappaB signal transduction / cellular response to nitric oxide / cysteine-type peptidase activity / cellular response to epidermal growth factor stimulus / regulation of cytokine production / cellular response to dexamethasone stimulus / protein maturation / proteolysis involved in protein catabolic process / T cell activation / enzyme activator activity / positive regulation of interleukin-1 beta production / negative regulation of extrinsic apoptotic signaling pathway / Regulation of NF-kappa B signaling / apoptotic signaling pathway / cellular response to estradiol stimulus / Regulation of TNFR1 signaling / wound healing / NOD1/2 Signaling Pathway / protein processing / positive regulation of neuron projection development / Regulation of necroptotic cell death / cellular response to insulin stimulus / cellular response to mechanical stimulus / positive regulation of NF-kappaB transcription factor activity / positive regulation of neuron apoptotic process / response to estradiol / lamellipodium / peptidase activity / heart development / cell body / protease binding / scaffold protein binding / angiogenesis / cellular response to hypoxia / response to lipopolysaccharide / response to ethanol / mitochondrial outer membrane / positive regulation of canonical NF-kappaB signal transduction / cytoskeleton / positive regulation of ERK1 and ERK2 cascade
Similarity search - Function
Caspase-8 / Death effector domain / Death effector domain (DED) profile. / Death effector domain / Death effector 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-8 / Death effector domain / Death effector domain (DED) profile. / Death effector domain / Death effector 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 / Caspase-8
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.97 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_39428.png

Downloads & links

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Map

FileDownload / File: emd_39428.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: 0.25
Minimum - Maximum-0.43255743 - 0.99293774
Average (Standard dev.)0.00039191917 (±0.032003403)
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_39428_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_39428_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Caspase-8/cFLIP death effector domain assembly

EntireName: Caspase-8/cFLIP death effector domain assembly
Components
  • Complex: 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

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

SupramoleculeName: 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: 4 / 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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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 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec.
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: 3.97 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 17838
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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