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- PDB-8yd7: Structure of FADD/Caspase-8/cFLIP death effector domain assembly -

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Basic information

Entry
Database: PDB / ID: 8yd7
TitleStructure of FADD/Caspase-8/cFLIP death effector domain assembly
Components
  • CASP8 and FADD-like apoptosis regulator subunit p12
  • Caspase-8Caspase 8
  • FAS-associated death domain protein
KeywordsAPOPTOSIS / FADD / Caspase-8 / cFLIP / death effector domain
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 / tumor necrosis factor receptor superfamily binding ...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 / tumor necrosis factor receptor superfamily binding / TRAIL signaling / CD95 death-inducing signaling complex / regulation of skeletal muscle satellite cell proliferation / ripoptosome / death-inducing signaling complex assembly / TRAIL-activated apoptotic signaling pathway / Defective RIPK1-mediated regulated necrosis / Apoptotic execution phase / 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 / 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 / caspase binding / positive regulation of macrophage differentiation / 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 / natural killer cell activation / CLEC7A/inflammasome pathway / receptor serine/threonine kinase binding / negative regulation of necroptotic process / activation of cysteine-type endopeptidase activity / positive regulation of innate immune response / 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 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 / TNFR1-induced proapoptotic signaling / motor neuron apoptotic process / 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 / Apoptotic cleavage of cellular proteins / pyroptotic inflammatory response / T cell homeostasis / 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 / enzyme activator activity / signaling adaptor activity / negative regulation of canonical NF-kappaB signal transduction / negative regulation of reactive oxygen species biosynthetic process / skeletal muscle tissue development / extrinsic apoptotic signaling pathway / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / keratinocyte differentiation / cysteine-type peptidase activity / extrinsic apoptotic signaling pathway in absence of ligand / spleen development / regulation of cytokine production / cellular response to epidermal growth factor stimulus / T cell activation / erythrocyte differentiation / cellular response to dexamethasone stimulus / proteolysis involved in protein catabolic process / 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
SELENIUM ATOM / CASP8 and FADD-like apoptosis regulator / FAS-associated death domain protein / Caspase-8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / SAD / Resolution: 3.32 Å
AuthorsLin, S.-C. / Yang, C.-Y.
Funding support Taiwan, 1items
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 19, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 15, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
G: CASP8 and FADD-like apoptosis regulator subunit p12
D: Caspase-8
C: Caspase-8
B: Caspase-8
E: Caspase-8
H: CASP8 and FADD-like apoptosis regulator subunit p12
I: CASP8 and FADD-like apoptosis regulator subunit p12
K: CASP8 and FADD-like apoptosis regulator subunit p12
L: FAS-associated death domain protein
A: Caspase-8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)220,62711
Polymers220,54910
Non-polymers791
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, light scattering
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)113.936, 150.057, 175.703
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and resid 2 through 181)
d_2ens_1(chain "B" and resid 2 through 181)
d_3ens_1(chain "C" and resid 2 through 181)
d_4ens_1(chain "D" and resid 2 through 181)
d_5ens_1chain "E"
d_1ens_2(chain "G" and (resid 2 through 120 or resid 127 through 175))
d_2ens_2(chain "H" and (resid 2 through 120 or resid 127 through 175))
d_3ens_2(chain "I" and (resid 2 through 120 or resid 127 through 175))
d_4ens_2(chain "K" and resid 2 through 175)

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1ASPASPPHEPHEAJ2 - 1812 - 181
d_21ens_1ASPASPPHEPHEBD2 - 1812 - 181
d_31ens_1ASPASPPHEPHECC2 - 1812 - 181
d_41ens_1ASPASPPHEPHEDB2 - 1812 - 181
d_51ens_1ASPASPPHEPHEEE2 - 1812 - 181
d_11ens_2SERSERMSEMSEGA2 - 1202 - 120
d_12ens_2LYSLYSVALVALGA127 - 175127 - 175
d_21ens_2SERSERMSEMSEHF2 - 1202 - 120
d_22ens_2LYSLYSVALVALHF127 - 175127 - 175
d_31ens_2SERSERMSEMSEIG2 - 1202 - 120
d_32ens_2LYSLYSVALVALIG127 - 175127 - 175
d_41ens_2SERSERVALVALKH2 - 1752 - 175

NCS ensembles :
ID
ens_1
ens_2

NCS oper:
IDCodeMatrixVector
1given(0.311734195671, 0.392027130053, -0.86552673012), (-0.322429315492, 0.900513194518, 0.291745305036), (0.893790315321, 0.188124203126, 0.407121795581)34.9011028693, 33.9237000495, -51.852344927
2given(-0.807848946441, 0.2999562645, -0.507352263345), (-0.152731832758, 0.724865229881, 0.671746518988), (0.569256591526, 0.620158558674, -0.539768742247)104.686819564, 40.3815796244, -35.9740150094
3given(-0.810420129326, -0.155158912192, 0.564929133565), (0.328889197996, 0.677507304993, 0.657887336193), (-0.484820698221, 0.718964229742, -0.498035467539)114.740915406, 24.9589684541, 28.2736027268
4given(0.36517382364, -0.398918410275, 0.84113743257), (0.481252414988, 0.854332702211, 0.196244100552), (-0.796896600317, 0.333136212196, 0.503960387856)51.5437687093, 24.415357657, 58.5933243529
5given(-0.569485270503, -0.272889007442, 0.775382561255), (0.36277634297, 0.763013842011, 0.534979627538), (-0.737617686652, 0.585953467877, -0.335527468058)100.830967613, -18.5198885807, 33.3502829869
6given(0.347888792693, 0.405763905319, -0.845179886804), (-0.386036465561, 0.883519452497, 0.265271981778), (0.854370666149, 0.233985106789, 0.464006179512)32.2999518029, 38.8274769502, -54.3177548969
7given(-0.772540490195, 0.303704028041, -0.557624474321), (-0.223901890542, 0.691491293076, 0.686809824487), (0.594179378994, 0.655441572492, -0.466205116475)104.881171457, 45.1218016117, -41.2920126168

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Components

#1: Protein
CASP8 and FADD-like apoptosis regulator subunit p12


Mass: 21078.756 Da / Num. of mol.: 4 / Mutation: H7G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CFLAR, CASH, CASP8AP1, CLARP, MRIT / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: O15519
#2: Protein
Caspase-8 / Caspase 8 / CASP-8 / Apoptotic cysteine protease / Apoptotic protease Mch-5 / CAP4 / FADD-homologous ICE/ced-3- ...CASP-8 / Apoptotic cysteine protease / Apoptotic protease Mch-5 / CAP4 / FADD-homologous ICE/ced-3-like protease / FADD-like ICE / FLICE / ICE-like apoptotic protease 5 / MORT1-associated ced-3 homolog / MACH


Mass: 22339.715 Da / Num. of mol.: 5 / Mutation: F122G,L123G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP8, MCH5 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: Q14790, caspase-8
#3: Protein FAS-associated death domain protein / FAS-associating death domain-containing protein / Growth-inhibiting gene 3 protein / Mediator of ...FAS-associating death domain-containing protein / Growth-inhibiting gene 3 protein / Mediator of receptor induced toxicity


Mass: 24534.912 Da / Num. of mol.: 1 / Mutation: H9G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FADD, MORT1, GIG3 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: Q13158
#4: Chemical ChemComp-SE / SELENIUM ATOM / Hydrogen selenide


Mass: 78.960 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Se
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.41 Å3/Da / Density % sol: 65 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / Details: HEPES, TBG, PEG8000, TCEP, sodium chloride / PH range: 7-9

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: BL13B1 / Wavelength: 0.97939 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 27, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97939 Å / Relative weight: 1
ReflectionResolution: 3.32→30 Å / Num. obs: 44899 / % possible obs: 99.5 % / Redundancy: 9.6 % / Biso Wilson estimate: 101.38 Å2 / Rmerge(I) obs: 0.124 / Rsym value: 0.124 / Net I/σ(I): 20.228
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) allΧ2% possible all
3.32-3.4410.70.55444400.9550.9880.1750.5821.09100
3.44-3.5810.70.37344580.9830.9960.1180.3921.093100
3.58-3.7410.60.28344590.9860.9970.0890.2971.116100
3.74-3.9410.50.19544700.9930.9980.0620.2041.119100
3.94-4.1810.10.13444530.9960.9990.0440.1411.09100
4.18-4.59.80.11744720.9960.9990.0390.1231.17599.9
4.5-4.959.30.09845170.9970.9990.0340.1041.30999.8
4.95-5.679.30.10445020.9950.9990.0350.111.5899.6
5.67-7.1290.11145440.9940.9990.0380.1172.28899.3
7.12-306.50.07645840.9930.9980.0330.0844.90496.2

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-2000data scaling
HKL-2000data reduction
AutoSolphasing
RefinementMethod to determine structure: SAD / Resolution: 3.32→29.81 Å / SU ML: 0.4268 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.4882
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.2311 2197 4.91 %5
Rwork0.1939 42575 --
obs0.1957 44772 99.2 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 112.37 Å2
Refinement stepCycle: LAST / Resolution: 3.32→29.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13821 0 1 0 13822
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.001713962
X-RAY DIFFRACTIONf_angle_d0.428118690
X-RAY DIFFRACTIONf_chiral_restr0.03582154
X-RAY DIFFRACTIONf_plane_restr0.00272387
X-RAY DIFFRACTIONf_dihedral_angle_d3.18741846
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2JAX-RAY DIFFRACTIONTorsion NCS1.13365277301
ens_1d_3JAX-RAY DIFFRACTIONTorsion NCS1.11025999984
ens_1d_4JAX-RAY DIFFRACTIONTorsion NCS1.1139224139
ens_1d_5JAX-RAY DIFFRACTIONTorsion NCS1.2302074176
ens_2d_2AGX-RAY DIFFRACTIONTorsion NCS1.26311598066
ens_2d_3AGX-RAY DIFFRACTIONTorsion NCS1.21138443248
ens_2d_4AGX-RAY DIFFRACTIONTorsion NCS1.14878325927
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.32-3.390.39341220.32212580X-RAY DIFFRACTION97.33
3.39-3.470.33861100.28572654X-RAY DIFFRACTION99.75
3.47-3.560.33861450.24842666X-RAY DIFFRACTION99.75
3.56-3.650.26851370.22772630X-RAY DIFFRACTION99.89
3.65-3.760.29381550.22812607X-RAY DIFFRACTION99.78
3.76-3.880.26971160.22342672X-RAY DIFFRACTION99.82
3.88-4.020.23761420.20572657X-RAY DIFFRACTION99.93
4.02-4.180.21541350.17592661X-RAY DIFFRACTION99.82
4.18-4.370.23431450.18242653X-RAY DIFFRACTION99.93
4.37-4.60.20691590.17232642X-RAY DIFFRACTION99.82
4.6-4.890.22271480.1682657X-RAY DIFFRACTION99.72
4.89-5.260.23861440.17512666X-RAY DIFFRACTION99.57
5.26-5.790.24811130.2092711X-RAY DIFFRACTION99.51
5.79-6.620.26361370.22492693X-RAY DIFFRACTION99.3
6.62-8.310.20611370.19722717X-RAY DIFFRACTION98.28
8.31-29.810.18061520.15632709X-RAY DIFFRACTION95.43

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