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- EMDB-6691: Apaf-1-Caspase-9 holoenzyme -

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Basic information

Entry
Database: EMDB / ID: EMD-6691
TitleApaf-1-Caspase-9 holoenzyme
Map dataNone
Sample
  • Complex: Apaf-1 apoptosome
Function / homology
Function and homology information


caspase-9 / response to G1 DNA damage checkpoint signaling / caspase complex / cytochrome c-heme linkage / regulation of apoptotic DNA fragmentation / Formation of apoptosome / apoptosome / cytochrome complex / activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c / leukocyte apoptotic process ...caspase-9 / response to G1 DNA damage checkpoint signaling / caspase complex / cytochrome c-heme linkage / regulation of apoptotic DNA fragmentation / Formation of apoptosome / apoptosome / cytochrome complex / activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c / leukocyte apoptotic process / glial cell apoptotic process / response to cobalt ion / cysteine-type endopeptidase activity involved in apoptotic signaling pathway / positive regulation of cysteine-type endopeptidase activity / Caspase activation via Dependence Receptors in the absence of ligand / Regulation of the apoptosome activity / Activation of caspases through apoptosome-mediated cleavage / cysteine-type endopeptidase activity involved in apoptotic process / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / mitochondrial electron transport, cytochrome c to oxygen / epithelial cell apoptotic process / fibroblast apoptotic process / AKT phosphorylates targets in the cytosol / mitochondrial electron transport, ubiquinol to cytochrome c / platelet formation / TP53 Regulates Transcription of Caspase Activators and Caspases / Transcriptional Regulation by E2F6 / Constitutive Signaling by AKT1 E17K in Cancer / cysteine-type endopeptidase activator activity involved in apoptotic process / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / protein maturation / enzyme activator activity / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / respirasome / signal transduction in response to DNA damage / forebrain development / positive regulation of apoptotic signaling pathway / cardiac muscle cell apoptotic process / cellular response to transforming growth factor beta stimulus / heat shock protein binding / cellular response to dexamethasone stimulus / intrinsic apoptotic signaling pathway / response to nutrient / kidney development / neural tube closure / response to ischemia / ADP binding / NOD1/2 Signaling Pathway / mitochondrial intermembrane space / protein processing / SH3 domain binding / activation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of neuron apoptotic process / cellular response to UV / intrinsic apoptotic signaling pathway in response to DNA damage / response to estradiol / nervous system development / peptidase activity / neuron apoptotic process / regulation of apoptotic process / secretory granule lumen / ficolin-1-rich granule lumen / response to lipopolysaccharide / electron transfer activity / cell differentiation / response to hypoxia / positive regulation of apoptotic process / cysteine-type endopeptidase activity / nucleotide binding / lipid binding / apoptotic process / DNA damage response / heme binding / Neutrophil degranulation / protein kinase binding / protein-containing complex / mitochondrion / proteolysis / extracellular exosome / extracellular region / ATP binding / identical protein binding / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
CASP9, CARD domain / Apoptotic Protease-Activating Factor 1, CARD domain / : / Apoptotic protease-activating factor 1-like, winged-helix domain / Apoptotic protease-activating factor 1 / APAF-1 helical domain / APAF-1 helical domain / Peptidase C14 family / Apoptotic protease-activating factors, helical domain / NB-ARC ...CASP9, CARD domain / Apoptotic Protease-Activating Factor 1, CARD domain / : / Apoptotic protease-activating factor 1-like, winged-helix domain / Apoptotic protease-activating factor 1 / APAF-1 helical domain / APAF-1 helical domain / Peptidase C14 family / Apoptotic protease-activating factors, helical domain / NB-ARC / NB-ARC domain / Caspase recruitment domain / Cytochrome c, class IA/ IB / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment 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. / Cytochrome c / : / Caspase domain / Caspase-like domain superfamily / Cytochrome c family profile. / Cytochrome c-like domain / Cytochrome c-like domain superfamily / Death-like domain superfamily / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Winged helix-like DNA-binding domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
cDNA FLJ75893, highly similar to Homo sapiens caspase 9, apoptosis-related cysteine peptidase (CASP9), transcript variant alpha, mRNA / Apoptotic protease-activating factor 1 / Cytochrome c / Caspase-9
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.4 Å
AuthorsLi Y / Zhou M / Hu Q / Shi Y
CitationJournal: Proc Natl Acad Sci U S A / Year: 2017
Title: Mechanistic insights into caspase-9 activation by the structure of the apoptosome holoenzyme.
Authors: Yini Li / Mengying Zhou / Qi Hu / Xiao-Chen Bai / Weiyun Huang / Sjors H W Scheres / Yigong Shi /
Abstract: Mammalian intrinsic apoptosis requires activation of the initiator caspase-9, which then cleaves and activates the effector caspases to execute cell killing. The heptameric Apaf-1 apoptosome is ...Mammalian intrinsic apoptosis requires activation of the initiator caspase-9, which then cleaves and activates the effector caspases to execute cell killing. The heptameric Apaf-1 apoptosome is indispensable for caspase-9 activation by together forming a holoenzyme. The molecular mechanism of caspase-9 activation remains largely enigmatic. Here, we report the cryoelectron microscopy (cryo-EM) structure of an apoptotic holoenzyme and structure-guided biochemical analyses. The caspase recruitment domains (CARDs) of Apaf-1 and caspase-9 assemble in two different ways: a 4:4 complex docks onto the central hub of the apoptosome, and a 2:1 complex binds the periphery of the central hub. The interface between the CARD complex and the central hub is required for caspase-9 activation within the holoenzyme. Unexpectedly, the CARD of free caspase-9 strongly inhibits its proteolytic activity. These structural and biochemical findings demonstrate that the apoptosome activates caspase-9 at least in part through sequestration of the inhibitory CARD domain.
History
DepositionDec 24, 2016-
Header (metadata) releaseJan 18, 2017-
Map releaseMar 1, 2017-
UpdateMar 1, 2017-
Current statusMar 1, 2017Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0563
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0563
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_6691.png

Downloads & links

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Map

FileDownload / File: emd_6691.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationNone
Voxel sizeX=Y=Z: 1.34 Å
Density
Contour LevelBy AUTHOR: 0.0563 / Movie #1: 0.0563
Minimum - Maximum-0.21274799 - 0.48513398
Average (Standard dev.)0.0012616193 (±0.01155583)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 428.80002 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.341.341.34
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z428.800428.800428.800
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.2130.4850.001

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Supplemental data

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Sample components

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Entire : Apaf-1 apoptosome

EntireName: Apaf-1 apoptosome
Components
  • Complex: Apaf-1 apoptosome

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Supramolecule #1: Apaf-1 apoptosome

SupramoleculeName: Apaf-1 apoptosome / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#7
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Insect cell expression vector pTIE1 (others) / Recombinant plasmid: pFasBac

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI POLARA 300
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: FEI FALCON II (4k x 4k) / Average electron dose: 32.0 e/Å2
Experimental equipment
Model: Tecnai Polara / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 240130

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