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- PDB-8e2i: Cryo-EM structure of BIRC6/Smac -

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Basic information

Entry
Database: PDB / ID: 8e2i
TitleCryo-EM structure of BIRC6/Smac
Components
  • (Baculoviral IAP repeat-containing protein 6) x 2
  • Diablo IAP-binding mitochondrial protein
KeywordsLIGASE / Ubiquitin / E3 ligase / Apoptosis / Autophagy / IAP
Function / homology
Function and homology information


Release of apoptotic factors from the mitochondria / CD40 receptor complex / labyrinthine layer development / (E3-independent) E2 ubiquitin-conjugating enzyme / ALK mutants bind TKIs / SMAC, XIAP-regulated apoptotic response / Regulation of the apoptosome activity / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / Flemming body ...Release of apoptotic factors from the mitochondria / CD40 receptor complex / labyrinthine layer development / (E3-independent) E2 ubiquitin-conjugating enzyme / ALK mutants bind TKIs / SMAC, XIAP-regulated apoptotic response / Regulation of the apoptosome activity / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / Flemming body / intrinsic apoptotic signaling pathway in response to oxidative stress / ubiquitin conjugating enzyme activity / microtubule organizing center / extrinsic apoptotic signaling pathway via death domain receptors / cysteine-type endopeptidase inhibitor activity / intrinsic apoptotic signaling pathway / regulation of cytokinesis / negative regulation of extrinsic apoptotic signaling pathway / apoptotic signaling pathway / trans-Golgi network / mitochondrial intermembrane space / cytoplasmic side of plasma membrane / spindle pole / ubiquitin-protein transferase activity / Signaling by ALK fusions and activated point mutants / regulation of cell population proliferation / neuron apoptotic process / midbody / cell population proliferation / protein phosphorylation / endosome / protein ubiquitination / positive regulation of apoptotic process / cell division / positive regulation of cell population proliferation / apoptotic process / centrosome / negative regulation of apoptotic process / mitochondrion / metal ion binding / nucleus / membrane / cytosol
Similarity search - Function
Smac/DIABLO-like superfamily / Smac/DIABLO protein / Second Mitochondria-derived Activator of Caspases / Baculoviral IAP repeat-containing protein 6 / Baculoviral IAP repeat-containing protein 6 / BIR repeat / Inhibitor of Apoptosis domain / BIR repeat profile. / Baculoviral inhibition of apoptosis protein repeat / Ubiquitin-conjugating enzyme E2 ...Smac/DIABLO-like superfamily / Smac/DIABLO protein / Second Mitochondria-derived Activator of Caspases / Baculoviral IAP repeat-containing protein 6 / Baculoviral IAP repeat-containing protein 6 / BIR repeat / Inhibitor of Apoptosis domain / BIR repeat profile. / Baculoviral inhibition of apoptosis protein repeat / Ubiquitin-conjugating enzyme E2 / Ubiquitin-conjugating enzyme / Ubiquitin-conjugating (UBC) core domain profile. / Ubiquitin-conjugating enzyme E2, catalytic domain homologues / Ubiquitin-conjugating enzyme/RWD-like
Similarity search - Domain/homology
Dual E2 ubiquitin-conjugating enzyme/E3 ubiquitin-protein ligase BIRC6 / Diablo IAP-binding mitochondrial protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.04 Å
AuthorsHunkeler, M. / Fischer, E.S.
Funding support United States, 2items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 15, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 22, 2023Group: Database references / Category: citation
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 29, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID
Revision 1.3Jun 12, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Baculoviral IAP repeat-containing protein 6
B: Baculoviral IAP repeat-containing protein 6
F: Diablo IAP-binding mitochondrial protein
E: Diablo IAP-binding mitochondrial protein
C: Baculoviral IAP repeat-containing protein 6
D: Baculoviral IAP repeat-containing protein 6


Theoretical massNumber of molelcules
Total (without water)1,122,3786
Polymers1,122,3786
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Baculoviral IAP repeat-containing protein 6 / BIR repeat-containing ubiquitin-conjugating enzyme / BRUCE / RING-type E3 ubiquitin transferase ...BIR repeat-containing ubiquitin-conjugating enzyme / BRUCE / RING-type E3 ubiquitin transferase BIRC6 / Ubiquitin-conjugating BIR domain enzyme apollon / APOLLON


Mass: 534158.312 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BIRC6, KIAA1289 / Cell line (production host): Expi293 / Production host: Homo sapiens (human) / References: UniProt: Q9NR09, Ligases
#2: Protein Diablo IAP-binding mitochondrial protein / Diablo homolog / mitochondrial / Direct IAP-binding protein with low pI / Second mitochondria- ...Diablo homolog / mitochondrial / Direct IAP-binding protein with low pI / Second mitochondria-derived activator of caspase / Smac


Mass: 22161.615 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DIABLO, SMAC / Production host: Escherichia coli (E. coli) / Strain (production host): LOBSTR / References: UniProt: Q9NR28
#3: Protein Baculoviral IAP repeat-containing protein 6


Mass: 4868.993 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): Expi293 / Production host: Homo sapiens (human)

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Baculoviral IAP repeat-containing protein 6 / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightValue: 1.111 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Strain: Expi293
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
130 mMHEPESC8H18N2O4S1
2150 mMSodium chlorideNaCl1
33 mMTCEPC9H15O6P1
SpecimenConc.: 1.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: added CHAPSO to 0.5 mM
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 283.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Details: Data collection in counting mode, using multi-shot scheme (9 holes per stage position, 3 movies per hole)
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 1.365 sec. / Electron dose: 56.379 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 14574
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV
Image scansWidth: 5760 / Height: 4092 / Movie frames/image: 50 / Used frames/image: 1-50

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameVersionCategory
2SerialEM3.8.5image acquisition
4cryoSPARCCTF correction
7Cootmodel fitting
9Cootmodel refinement
10PHENIXmodel refinement
11ISOLDEmodel refinement
12UCSF ChimeraXmodel refinement
13UCSF Chimeramodel refinement
14cryoSPARCinitial Euler assignment
15cryoSPARCfinal Euler assignment
16cryoSPARCclassification
17cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 3192460
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.04 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 192025 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00447020
ELECTRON MICROSCOPYf_angle_d0.59163876
ELECTRON MICROSCOPYf_dihedral_angle_d15.4717072
ELECTRON MICROSCOPYf_chiral_restr0.0397744
ELECTRON MICROSCOPYf_plane_restr0.0057998

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