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- PDB-8e2k: Cryo-EM structure of BIRC6/HtrA2-S306A -

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Basic information

Entry
Database: PDB / ID: 8e2k
TitleCryo-EM structure of BIRC6/HtrA2-S306A
Components
  • Baculoviral IAP repeat-containing protein 6
  • Serine protease HTRA2, mitochondrial
KeywordsLIGASE / Ubiquitin / E3 ligase / Apoptosis / Autophagy / IAP
Function / homology
Function and homology information


HtrA2 peptidase / pentacyclic triterpenoid metabolic process / negative regulation of type 2 mitophagy / ceramide metabolic process / regulation of autophagy of mitochondrion / mitochondrial protein catabolic process / CD40 receptor complex / labyrinthine layer development / (E3-independent) E2 ubiquitin-conjugating enzyme / ALK mutants bind TKIs ...HtrA2 peptidase / pentacyclic triterpenoid metabolic process / negative regulation of type 2 mitophagy / ceramide metabolic process / regulation of autophagy of mitochondrion / mitochondrial protein catabolic process / CD40 receptor complex / labyrinthine layer development / (E3-independent) E2 ubiquitin-conjugating enzyme / ALK mutants bind TKIs / programmed cell death / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / serine-type endopeptidase complex / Flemming body / response to herbicide / protein serine/threonine kinase inhibitor activity / adult walking behavior / positive regulation of protein targeting to mitochondrion / execution phase of apoptosis / microtubule organizing center / ubiquitin conjugating enzyme activity / protein autoprocessing / positive regulation of execution phase of apoptosis / negative regulation of cell cycle / ubiquitin ligase inhibitor activity / regulation of multicellular organism growth / cysteine-type endopeptidase inhibitor activity / Mitochondrial unfolded protein response (UPRmt) / neuron development / cellular response to interferon-beta / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / forebrain development / cellular response to retinoic acid / Mitochondrial protein degradation / serine-type peptidase activity / regulation of cytokinesis / negative regulation of extrinsic apoptotic signaling pathway / mitochondrion organization / trans-Golgi network / protein catabolic process / mitochondrial membrane / cellular response to growth factor stimulus / mitochondrial intermembrane space / cytoplasmic side of plasma membrane / intrinsic apoptotic signaling pathway in response to DNA damage / spindle pole / ubiquitin-protein transferase activity / Signaling by ALK fusions and activated point mutants / unfolded protein binding / peptidase activity / regulation of cell population proliferation / cellular response to heat / midbody / cellular response to oxidative stress / neuron apoptotic process / negative regulation of neuron apoptotic process / cytoskeleton / cell population proliferation / endosome / intracellular signal transduction / protein ubiquitination / protein phosphorylation / positive regulation of apoptotic process / cell division / serine-type endopeptidase activity / apoptotic process / positive regulation of cell population proliferation / centrosome / endoplasmic reticulum membrane / negative regulation of apoptotic process / chromatin / endoplasmic reticulum / mitochondrion / proteolysis / metal ion binding / identical protein binding / nucleus / membrane / cytosol
Similarity search - Function
Baculoviral IAP repeat-containing protein 6 / Baculoviral IAP repeat-containing protein 6 / PDZ domain 6 / PDZ domain / Peptidase S1C / Trypsin-like peptidase domain / BIR repeat / Inhibitor of Apoptosis domain / BIR repeat profile. / Baculoviral inhibition of apoptosis protein repeat ...Baculoviral IAP repeat-containing protein 6 / Baculoviral IAP repeat-containing protein 6 / PDZ domain 6 / PDZ domain / Peptidase S1C / Trypsin-like peptidase domain / 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 / PDZ domain profile. / Domain present in PSD-95, Dlg, and ZO-1/2. / PDZ domain / PDZ superfamily / Peptidase S1, PA clan
Similarity search - Domain/homology
Serine protease HTRA2, mitochondrial / 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: 3.21 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
X: Serine protease HTRA2, mitochondrial
Y: Serine protease HTRA2, mitochondrial
Z: Serine protease HTRA2, mitochondrial


Theoretical massNumber of molelcules
Total (without water)1,178,5205
Polymers1,178,5205
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: 535317.188 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BIRC6, KIAA1289 / Production host: Homo sapiens (human) / Strain (production host): Expi293 / References: UniProt: Q9NR09, Ligases
#2: Protein Serine protease HTRA2, mitochondrial / High temperature requirement protein A2 / HtrA2 / Omi stress-regulated endoprotease / Serine ...High temperature requirement protein A2 / HtrA2 / Omi stress-regulated endoprotease / Serine protease 25 / Serine proteinase OMI


Mass: 35961.887 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HTRA2, OMI, PRSS25 / Production host: Escherichia coli (E. coli) / Strain (production host): LOBSTR / References: UniProt: O43464, HtrA2 peptidase

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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: 1.174 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 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: added CHAPSO to 0.4 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: 2100 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: 2.5 sec. / Electron dose: 60.659 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 15309
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
4CTFFINDCTF correction
5RELIONCTF correction
8Cootmodel fitting
10Cootmodel refinement
11PHENIXmodel refinement
12ISOLDEmodel refinement
13UCSF ChimeraXmodel refinement
14UCSF Chimeramodel refinement
15cryoSPARCinitial Euler assignment
16cryoSPARCfinal Euler assignment
17cryoSPARCclassification
18cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2049607
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.21 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 73712 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00448803
ELECTRON MICROSCOPYf_angle_d0.61266318
ELECTRON MICROSCOPYf_dihedral_angle_d15.38917779
ELECTRON MICROSCOPYf_chiral_restr0.0418032
ELECTRON MICROSCOPYf_plane_restr0.0068322

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