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- PDB-8atm: Structure of the giant inhibitor of apoptosis, BIRC6 (composite map) -

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Basic information

Entry
Database: PDB / ID: 8atm
TitleStructure of the giant inhibitor of apoptosis, BIRC6 (composite map)
ComponentsBaculoviral IAP repeat-containing protein 6
KeywordsAPOPTOSIS / E2/E3 ubiquitin ligase
Function / homology
Function and homology information


labyrinthine layer development / (E3-independent) E2 ubiquitin-conjugating enzyme / ALK mutants bind TKIs / Flemming body / microtubule organizing center / ubiquitin conjugating enzyme activity / cysteine-type endopeptidase inhibitor activity / regulation of cytokinesis / negative regulation of extrinsic apoptotic signaling pathway / trans-Golgi network ...labyrinthine layer development / (E3-independent) E2 ubiquitin-conjugating enzyme / ALK mutants bind TKIs / Flemming body / microtubule organizing center / ubiquitin conjugating enzyme activity / cysteine-type endopeptidase inhibitor activity / regulation of cytokinesis / negative regulation of extrinsic apoptotic signaling pathway / trans-Golgi network / spindle pole / ubiquitin-protein transferase activity / Signaling by ALK fusions and activated point mutants / regulation of cell population proliferation / midbody / cell population proliferation / endosome / protein ubiquitination / protein phosphorylation / cell division / apoptotic process / positive regulation of cell population proliferation / centrosome / negative regulation of apoptotic process / metal ion binding / nucleus / membrane / cytosol
Similarity search - Function
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
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsDietz, L. / Elliott, P.R.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MR/R008582/1 United Kingdom
CitationJournal: Science / Year: 2023
Title: Structural basis for SMAC-mediated antagonism of caspase inhibition by the giant ubiquitin ligase BIRC6.
Authors: Larissa Dietz / Cara J Ellison / Carlos Riechmann / C Keith Cassidy / F Daniel Felfoldi / Adán Pinto-Fernández / Benedikt M Kessler / Paul R Elliott /
Abstract: Certain inhibitor of apoptosis (IAP) family members are sentinel proteins that prevent untimely cell death by inhibiting caspases. Antagonists, including second mitochondria-derived activator of ...Certain inhibitor of apoptosis (IAP) family members are sentinel proteins that prevent untimely cell death by inhibiting caspases. Antagonists, including second mitochondria-derived activator of caspases (SMAC), regulate IAPs and drive cell death. Baculoviral IAP repeat-containing protein 6 (BIRC6), a giant IAP with dual E2 and E3 ubiquitin ligase activity, regulates programmed cell death through unknown mechanisms. We show that BIRC6 directly restricts executioner caspase-3 and -7 and ubiquitinates caspase-3, -7, and -9, working exclusively with noncanonical E1, UBA6. Notably, we show that SMAC suppresses both mechanisms. Cryo-electron microscopy structures of BIRC6 alone and in complex with SMAC reveal that BIRC6 is an antiparallel dimer juxtaposing the substrate-binding module against the catalytic domain. Furthermore, we discover that SMAC multisite binding to BIRC6 results in a subnanomolar affinity interaction, enabling SMAC to competitively displace caspases, thus antagonizing BIRC6 anticaspase function.
History
DepositionAug 23, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 8, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 15, 2023Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
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_author.identifier_ORCID
Revision 1.3Jul 24, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Baculoviral IAP repeat-containing protein 6
B: Baculoviral IAP repeat-containing protein 6


Theoretical massNumber of molelcules
Total (without water)1,061,9542
Polymers1,061,9542
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: light scattering, Dimer in solution confirmed via SEC-MALS
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area20770 Å2
ΔGint-117 kcal/mol
Surface area178080 Å2
MethodPISA

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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: 530977.000 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BIRC6, KIAA1289 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9NR09, RING-type E3 ubiquitin transferase

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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: Anti-parallel homodimer / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 1 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenConc.: 4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
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: 2500 nm / Nominal defocus min: 1000 nm / Calibrated defocus min: 1000 nm / Calibrated defocus max: 2500 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 3.5 sec. / Electron dose: 49.9 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
4CTFFINDCTF correction
9PHENIXmodel refinement
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 548509
3D reconstructionResolution: 3.3 Å / Resolution method: OTHER / Num. of particles: 127710
Details: Derived from a composite map. See individual multibody maps for resolution.
Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL

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