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Yorodumi- EMDB-39427: Structure of the Caspase-8/cFLIP death effector domain assembly -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-39427 | |||||||||
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Title | Structure of the Caspase-8/cFLIP death effector domain assembly | |||||||||
Map data | ||||||||||
Sample |
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Keywords | FADD / 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 / 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 ...negative regulation of myoblast fusion / 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 / ripoptosome / Defective RIPK1-mediated regulated necrosis / Apoptotic execution phase / TRAIL-activated apoptotic signaling pathway / Activation, myristolyation of BID and translocation to mitochondria / 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 / Caspase activation via Death Receptors in the presence of ligand / positive regulation of extracellular matrix organization / positive regulation of macrophage differentiation / positive regulation of glomerular mesangial cell proliferation / self proteolysis / response to cobalt ion / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / : / skeletal muscle tissue regeneration / death-inducing signaling complex / negative regulation of hepatocyte apoptotic process / CLEC7A/inflammasome pathway / negative regulation of necroptotic process / natural killer cell activation / : / activation of cysteine-type endopeptidase activity / regulation of tumor necrosis factor-mediated signaling pathway / tumor necrosis factor receptor binding / death receptor binding / positive regulation of hepatocyte proliferation / : / 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 / protein maturation / cellular response to organic cyclic compound / extrinsic apoptotic signaling pathway via death domain receptors / cellular response to nitric oxide / Caspase-mediated cleavage of cytoskeletal proteins / response to tumor necrosis factor / negative regulation of canonical NF-kappaB signal transduction / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of reactive oxygen species biosynthetic process / cysteine-type peptidase activity / skeletal muscle tissue development / keratinocyte differentiation / extrinsic apoptotic signaling pathway / enzyme activator activity / regulation of cytokine production / cellular response to epidermal growth factor stimulus / cellular response to dexamethasone stimulus / erythrocyte differentiation / T cell activation / proteolysis involved in protein catabolic process / positive regulation of interleukin-1 beta production / apoptotic signaling pathway / cellular response to estradiol stimulus / Regulation of NF-kappa B signaling / negative regulation of extrinsic apoptotic signaling pathway / Regulation of TNFR1 signaling / wound healing / NOD1/2 Signaling Pathway / Regulation of necroptotic cell death / neuron differentiation / positive regulation of neuron projection development / cellular response to mechanical stimulus / cellular response to insulin stimulus / positive regulation of neuron apoptotic process / lamellipodium / response to estradiol / peptidase activity / positive regulation of NF-kappaB transcription factor activity / heart development / cellular response to hypoxia / cell body / scaffold protein binding / protease binding / angiogenesis / positive regulation of canonical NF-kappaB signal transduction Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.49 Å | |||||||||
Authors | Lin S-C / Yang C-Y | |||||||||
Funding support | Taiwan, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_39427.map.gz | 70.3 MB | EMDB map data format | |
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Header (meta data) | emd-39427-v30.xml emd-39427.xml | 17.3 KB 17.3 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_39427_fsc.xml | 11 KB | Display | FSC data file |
Images | emd_39427.png | 30.7 KB | ||
Filedesc metadata | emd-39427.cif.gz | 6 KB | ||
Others | emd_39427_half_map_1.map.gz emd_39427_half_map_2.map.gz | 127.1 MB 127.1 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-39427 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-39427 | HTTPS FTP |
-Validation report
Summary document | emd_39427_validation.pdf.gz | 1.1 MB | Display | EMDB validaton report |
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Full document | emd_39427_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | emd_39427_validation.xml.gz | 19.8 KB | Display | |
Data in CIF | emd_39427_validation.cif.gz | 25.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-39427 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-39427 | HTTPS FTP |
-Related structure data
Related structure data | 8ynmMC 8ym4C 8ym5C 8ym6C 8yniC 8ynkC 8ynlC 8ynnC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_39427.map.gz / Format: CCP4 / Size: 137.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.84 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_39427_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_39427_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Caspase-8/cFLIP death effector domain assembly
Entire | Name: Caspase-8/cFLIP death effector domain assembly |
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Components |
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-Supramolecule #1: Caspase-8/cFLIP death effector domain assembly
Supramolecule | Name: Caspase-8/cFLIP death effector domain assembly / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: CASP8 and FADD-like apoptosis regulator subunit p43
Macromolecule | Name: CASP8 and FADD-like apoptosis regulator subunit p43 / type: protein_or_peptide / ID: 1 / Number of copies: 8 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 20.878479 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: 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 |
-Macromolecule #2: Caspase-8 subunit p10
Macromolecule | Name: Caspase-8 subunit p10 / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 55.191648 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: 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 |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 0.2 mg/mL | |||||||||
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Buffer | pH: 8 Component:
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Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY | |||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 279 K / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Software | Name: EPU |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 72.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination 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 stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |