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- EMDB-27838: Cryo-EM structure of BIRC6/Smac (from local refinement 1) -

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Basic information

Entry
Database: EMDB / ID: EMD-27838
TitleCryo-EM structure of BIRC6/Smac (from local refinement 1)
Map datamain map
Sample
  • Complex: Baculoviral IAP repeat-containing protein 6
    • Protein or peptide: Diablo IAP-binding mitochondrial protein
    • Protein or peptide: Baculoviral IAP repeat-containing protein 6
Function / homology
Function and homology information


activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c / Release of apoptotic factors from the mitochondria / CD40 receptor complex / SMAC, XIAP-regulated apoptotic response / Regulation of the apoptosome activity / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / intrinsic apoptotic signaling pathway in response to oxidative stress / extrinsic apoptotic signaling pathway via death domain receptors / intrinsic apoptotic signaling pathway ...activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c / Release of apoptotic factors from the mitochondria / CD40 receptor complex / SMAC, XIAP-regulated apoptotic response / Regulation of the apoptosome activity / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / intrinsic apoptotic signaling pathway in response to oxidative stress / extrinsic apoptotic signaling pathway via death domain receptors / intrinsic apoptotic signaling pathway / mitochondrial intermembrane space / cytoplasmic side of plasma membrane / activation of cysteine-type endopeptidase activity involved in apoptotic process / neuron apoptotic process / positive regulation of apoptotic process / apoptotic process / mitochondrion / cytosol
Similarity search - Function
Smac/DIABLO-like superfamily / Smac/DIABLO protein / Second Mitochondria-derived Activator of Caspases
Similarity search - Domain/homology
Diablo IAP-binding mitochondrial protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.44 Å
AuthorsHunkeler M / Fischer ES
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)CA066996 United States
The Mark Foundation19-001-ELA United States
CitationJournal: Science / Year: 2023
Title: Structures of BIRC6-client complexes provide a mechanism of SMAC-mediated release of caspases.
Authors: Moritz Hunkeler / Cyrus Y Jin / Eric S Fischer /
Abstract: Tight regulation of apoptosis is essential for metazoan development and prevents diseases such as cancer and neurodegeneration. Caspase activation is central to apoptosis, and inhibitor of apoptosis ...Tight regulation of apoptosis is essential for metazoan development and prevents diseases such as cancer and neurodegeneration. Caspase activation is central to apoptosis, and inhibitor of apoptosis proteins (IAPs) are the principal actors that restrain caspase activity and are therefore attractive therapeutic targets. IAPs, in turn, are regulated by mitochondria-derived proapoptotic factors such as SMAC and HTRA2. Through a series of cryo-electron microscopy structures of full-length human baculoviral IAP repeat-containing protein 6 (BIRC6) bound to SMAC, caspases, and HTRA2, we provide a molecular understanding for BIRC6-mediated caspase inhibition and its release by SMAC. The architecture of BIRC6, together with near-irreversible binding of SMAC, elucidates how the IAP inhibitor SMAC can effectively control a processive ubiquitin ligase to respond to apoptotic stimuli.
History
DepositionAug 15, 2022-
Header (metadata) releaseFeb 15, 2023-
Map releaseFeb 15, 2023-
UpdateMar 29, 2023-
Current statusMar 29, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27838.png

Downloads & links

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Map

FileDownload / File: emd_27838.map.gz / Format: CCP4 / Size: 166.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmain map
Voxel sizeX=Y=Z: 1.1995 Å
Density
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-0.93148196 - 1.3240911
Average (Standard dev.)-0.0013993931 (±0.03061946)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions352352352
Spacing352352352
CellA=B=C: 422.224 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_27838_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: mian map post-processed with deepEMhancer

Fileemd_27838_additional_1.map
Annotationmian map post-processed with deepEMhancer
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half-map 1

Fileemd_27838_half_map_1.map
Annotationhalf-map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 2

Fileemd_27838_half_map_2.map
Annotationhalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Baculoviral IAP repeat-containing protein 6

EntireName: Baculoviral IAP repeat-containing protein 6
Components
  • Complex: Baculoviral IAP repeat-containing protein 6
    • Protein or peptide: Diablo IAP-binding mitochondrial protein
    • Protein or peptide: Baculoviral IAP repeat-containing protein 6

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Supramolecule #1: Baculoviral IAP repeat-containing protein 6

SupramoleculeName: Baculoviral IAP repeat-containing protein 6 / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.111 MDa

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Macromolecule #1: Diablo IAP-binding mitochondrial protein

MacromoleculeName: Diablo IAP-binding mitochondrial protein / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.161615 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MAVPIAQKSE PHSLSSEALM RRAVSLVTDS TSTFLSQTTY ALIEAITEYT KAVYTLTSLY RQYTSLLGKM NSEEEDEVWQ VIIGARAEM TSKHQEYLKL ETTWMTAVGL SEMAAEAAYQ TGADQASITA RNHIQLVKLQ VEEVHQLSRK AETKLAEAQI E ELRQKTQE ...String:
MAVPIAQKSE PHSLSSEALM RRAVSLVTDS TSTFLSQTTY ALIEAITEYT KAVYTLTSLY RQYTSLLGKM NSEEEDEVWQ VIIGARAEM TSKHQEYLKL ETTWMTAVGL SEMAAEAAYQ TGADQASITA RNHIQLVKLQ VEEVHQLSRK AETKLAEAQI E ELRQKTQE EGEERAESEQ EAYLREDHHH HHHHHH

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Macromolecule #2: Baculoviral IAP repeat-containing protein 6

MacromoleculeName: Baculoviral IAP repeat-containing protein 6 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO / EC number: Ligases
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 4.868993 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) ...String:
(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)

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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

Concentration1.4 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
30.0 mMC8H18N2O4SHEPES
150.0 mMNaClSodium chlorideSodium chloride
3.0 mMC9H15O6PTCEP
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Support film - Film thickness: 12.0 nm / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 0.039 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 283.15 K / Instrument: LEICA EM GP
Detailsadded CHAPSO to 0.5 mM

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 105000
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
DetailsData collection in counting mode, using multi-shot scheme (9 holes per stage position, 3 movies per hole)
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 5760 pixel / Digitization - Dimensions - Height: 4092 pixel / Digitization - Frames/image: 1-50 / Number grids imaged: 1 / Number real images: 14574 / Average exposure time: 1.365 sec. / Average electron dose: 56.379 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3192460
Startup modelType of model: OTHER / Details: ab initio
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationNumber classes: 6 / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.44 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 192025
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: OTHER
Output model

PDB-8e2j:
Cryo-EM structure of BIRC6/Smac (from local refinement 1)

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