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- PDB-8auk: Cryo-EM structure of human BIRC6 in complex with HTRA2. -

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Basic information

Entry
Database: PDB / ID: 8auk
TitleCryo-EM structure of human BIRC6 in complex with HTRA2.
Components
  • Baculoviral IAP repeat-containing protein 6
  • Serine protease HTRA2, mitochondrial
KeywordsLIGASE / E3 ubiquitin ligase / E2/E3 hybrid / inhibitor of apoptosis protein
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: 6.2 Å
AuthorsEhrmann, J.F. / Grabarczyk, D.B. / Clausen, T.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
H2020 Marie Curie Actions of the European Commission847548European Union
CitationJournal: Science / Year: 2023
Title: Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex.
Authors: Julian F Ehrmann / Daniel B Grabarczyk / Maria Heinke / Luiza Deszcz / Robert Kurzbauer / Otto Hudecz / Alexandra Shulkina / Rebeca Gogova / Anton Meinhart / Gijs A Versteeg / Tim Clausen /
Abstract: Inhibitor of apoptosis proteins (IAPs) bind to pro-apoptotic proteases, keeping them inactive and preventing cell death. The atypical ubiquitin ligase BIRC6 is the only essential IAP, additionally ...Inhibitor of apoptosis proteins (IAPs) bind to pro-apoptotic proteases, keeping them inactive and preventing cell death. The atypical ubiquitin ligase BIRC6 is the only essential IAP, additionally functioning as a suppressor of autophagy. We performed a structure-function analysis of BIRC6 in complex with caspase-9, HTRA2, SMAC, and LC3B, which are critical apoptosis and autophagy proteins. Cryo-electron microscopy structures showed that BIRC6 forms a megadalton crescent shape that arcs around a spacious cavity containing receptor sites for client proteins. Multivalent binding of SMAC obstructs client binding, impeding ubiquitination of both autophagy and apoptotic substrates. On the basis of these data, we discuss how the BIRC6/SMAC complex can act as a stress-induced hub to regulate apoptosis and autophagy drivers.
History
DepositionAug 25, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 15, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 22, 2023Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _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_author.identifier_ORCID
Revision 1.3May 24, 2023Group: Structure summary / Category: struct / Item: _struct.title
Revision 1.4Jul 24, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / em_admin
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _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
D: Serine protease HTRA2, mitochondrial
E: Serine protease HTRA2, mitochondrial
C: Serine protease HTRA2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,169,1547
Polymers1,169,0235
Non-polymers1312
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area24730 Å2
ΔGint-130 kcal/mol
Surface area258130 Å2

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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: 532009.000 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BIRC6, KIAA1289 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q9NR09, RING-type E3 ubiquitin transferase
#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: 35001.820 Da / Num. of mol.: 3 / Mutation: S306A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HTRA2, OMI, PRSS25 / Production host: Escherichia coli (E. coli) / References: UniProt: O43464, HtrA2 peptidase
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
Has ligand of interestN

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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: Human BIRC6 homodimer in complex with HTRA2 homotrimer
Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Molecular weightValue: 1.17 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni, Escherichia coli
Buffer solutionpH: 7.5
SpecimenConc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 defocus max: 3000 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.20.1_4487refinement
PHENIX1.20.1_4487refinement
EM softwareName: RELION / Version: 4 / Category: 3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 6.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 15780 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
17VGE

7vge

17VGE1PDBexperimental model
28ATU

8atu

18ATU2PDBexperimental model
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 412.95 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.005548688
ELECTRON MICROSCOPYf_angle_d1.131366160
ELECTRON MICROSCOPYf_chiral_restr0.06288034
ELECTRON MICROSCOPYf_plane_restr0.00618301
ELECTRON MICROSCOPYf_dihedral_angle_d4.12376474

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