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- PDB-8ato: Structure of the giant inhibitor of apoptosis, BIRC6 bound to the... -

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Basic information

Entry
Database: PDB / ID: 8ato
TitleStructure of the giant inhibitor of apoptosis, BIRC6 bound to the regulator SMAC
Components
  • Baculoviral IAP repeat-containing protein 6
  • Diablo IAP-binding mitochondrial protein
KeywordsAPOPTOSIS / E2/E3 ubiquitin ligase
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 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)1,103,5284
Polymers1,103,5284
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: light scattering, SEC-MALS confirmed dimer in solution
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area23920 Å2
ΔGint-139 kcal/mol
Surface area278320 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
#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: 20787.098 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 BL21(DE3) (bacteria) / Strain (production host): Rosetta II DE3 / References: UniProt: Q9NR28

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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

Component
IDNameTypeEntity IDParent-IDSource
1Anti-parallel homodimerCOMPLEXall0MULTIPLE SOURCES
2Baculoviral IAP repeat-containing protein 6COMPLEX#11RECOMBINANT
3Diablo IAP-binding mitochondrial proteinCOMPLEX#21RECOMBINANT
Molecular weightValue: 1 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Spodoptera frugiperda (fall armyworm)7108
33Escherichia coli BL21(DE3) (bacteria)469008
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: 750 nm / Calibrated defocus min: 750 nm / Calibrated defocus max: 2500 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 2.3 sec. / Electron dose: 47.27 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.19.2_4158refinement
PHENIX1.19.2_4158refinement
EM software
IDNameCategory
4CTFFINDCTF correction
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1417739
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 36872 / Symmetry type: POINT
Atomic model buildingB value: 191.06 / Protocol: OTHER / Space: REAL
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 194.26 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.002447809
ELECTRON MICROSCOPYf_angle_d0.526764951
ELECTRON MICROSCOPYf_chiral_restr0.03877832
ELECTRON MICROSCOPYf_plane_restr0.00368162
ELECTRON MICROSCOPYf_dihedral_angle_d4.02056373

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