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Yorodumi- EMDB-39126: Structure of the FADD/Caspase-8/cFLIP death effector domain assembly -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-39126 | |||||||||
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Title | Structure of the FADD/Caspase-8/cFLIP death effector domain assembly | |||||||||
Map data | sharpened map | |||||||||
Sample |
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Keywords | FADD / 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 activation-induced cell death of T cells / negative regulation of myoblast fusion / skeletal myofibril assembly / caspase-8 / death effector domain binding / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / tumor necrosis factor receptor superfamily binding / FasL/ CD95L signaling / skeletal muscle atrophy ...positive regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation / negative regulation of activation-induced cell death of T cells / negative regulation of myoblast fusion / skeletal myofibril assembly / caspase-8 / death effector domain binding / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / tumor necrosis factor receptor superfamily binding / FasL/ CD95L signaling / skeletal muscle atrophy / TRAIL signaling / CD95 death-inducing signaling complex / death-inducing signaling complex assembly / 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 / positive regulation of adaptive immune response / regulation of necroptotic process / Caspase activation via Death Receptors in the presence of ligand / positive regulation of extracellular matrix organization / caspase binding / necroptotic signaling pathway / 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 / receptor serine/threonine kinase binding / CLEC7A/inflammasome pathway / negative regulation of necroptotic process / natural killer cell activation / positive regulation of innate immune response / : / activation of cysteine-type endopeptidase activity / regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of type I interferon-mediated signaling pathway / tumor necrosis factor receptor binding / death receptor binding / positive regulation of extrinsic apoptotic signaling pathway / positive regulation of hepatocyte proliferation / : / motor neuron apoptotic process / 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 / positive regulation of activated T cell proliferation / response to testosterone / T cell homeostasis / positive regulation of execution phase of apoptosis / B cell activation / positive regulation of proteolysis / behavioral response to cocaine / 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 / lymph node development / response to tumor necrosis factor / negative regulation of canonical NF-kappaB signal transduction / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / signaling adaptor activity / negative regulation of reactive oxygen species biosynthetic process / extrinsic apoptotic signaling pathway in absence of ligand / cysteine-type peptidase activity / skeletal muscle tissue development / spleen 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 / thymus development / proteolysis involved in protein catabolic process / positive regulation of interleukin-1 beta production / apoptotic signaling pathway / kidney development / positive regulation of interleukin-8 production Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.68 Å | |||||||||
Authors | Lin S-C / Yang C-Y | |||||||||
Funding support | Taiwan, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_39126.map.gz | 70.2 MB | EMDB map data format | |
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Header (meta data) | emd-39126-v30.xml emd-39126.xml | 18.8 KB 18.8 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_39126_fsc.xml | 11 KB | Display | FSC data file |
Images | emd_39126.png | 37.3 KB | ||
Filedesc metadata | emd-39126.cif.gz | 6.4 KB | ||
Others | emd_39126_half_map_1.map.gz emd_39126_half_map_2.map.gz | 127.1 MB 127.1 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-39126 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-39126 | HTTPS FTP |
-Validation report
Summary document | emd_39126_validation.pdf.gz | 1.1 MB | Display | EMDB validaton report |
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Full document | emd_39126_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | emd_39126_validation.xml.gz | 19.6 KB | Display | |
Data in CIF | emd_39126_validation.cif.gz | 25.1 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-39126 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-39126 | HTTPS FTP |
-Related structure data
Related structure data | 8ybxMC 8yd7C 8yd8C 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_39126.map.gz / Format: CCP4 / Size: 137.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Annotation | sharpened map | ||||||||||||||||||||||||||||||||||||
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_39126_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_39126_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : FADD/Caspase-8/cFLIP death effector domain assembly
Entire | Name: FADD/Caspase-8/cFLIP death effector domain assembly |
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Components |
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-Supramolecule #1: FADD/Caspase-8/cFLIP death effector domain assembly
Supramolecule | Name: FADD/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: Caspase-8 subunit p10
Macromolecule | Name: Caspase-8 subunit p10 / type: protein_or_peptide / ID: 1 / 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 BL21 (bacteria) |
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 |
-Macromolecule #2: CASP8 and FADD-like apoptosis regulator subunit p43
Macromolecule | Name: CASP8 and FADD-like apoptosis regulator subunit p43 / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 20.878479 KDa |
Recombinant expression | Organism: Escherichia coli BL21 (bacteria) |
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 #3: FAS-associated death domain protein
Macromolecule | Name: FAS-associated death domain protein / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 24.381533 KDa |
Recombinant expression | Organism: Escherichia coli BL21 (bacteria) |
Sequence | String: 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 |
-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 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR | |||||||||
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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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 |