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- PDB-8d9x: Cryo-EM structure of human DELE1 in oligomeric form -

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Basic information

Entry
Database: PDB / ID: 8d9x
TitleCryo-EM structure of human DELE1 in oligomeric form
ComponentsMaltodextrin-binding protein,DAP3-binding cell death enhancer 1 short form
KeywordsPROTEIN BINDING / Oligomer / Mitochondria / Integrated Stress Response / Kinase / Tetratricopeptide repeat
Function / homology
Function and homology information


HRI-mediated signaling / regulation of cysteine-type endopeptidase activity involved in apoptotic process / integrated stress response signaling / carbohydrate transmembrane transporter activity / extrinsic apoptotic signaling pathway via death domain receptors / protein serine/threonine kinase activator activity / outer membrane-bounded periplasmic space / mitochondrial inner membrane / protein kinase binding / mitochondrion / cytosol
Similarity search - Function
Sel1 repeat / Sel1-like repeat / Sel1-like repeats. / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / Tetratricopeptide-like helical domain superfamily
Similarity search - Domain/homology
Maltodextrin-binding protein / DAP3-binding cell death enhancer 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsYang, J. / Lander, G.C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) United States
CitationJournal: Nat Struct Mol Biol / Year: 2023
Title: DELE1 oligomerization promotes integrated stress response activation.
Authors: Jie Yang / Kelsey R Baron / Daniel E Pride / Anette Schneemann / Xiaoyan Guo / Wenqian Chen / Albert S Song / Giovanni Aviles / Martin Kampmann / R Luke Wiseman / Gabriel C Lander /
Abstract: Mitochondria are dynamic organelles that continually respond to cellular stress. Recent studies have demonstrated that mitochondrial stress is relayed from mitochondria to the cytosol by the release ...Mitochondria are dynamic organelles that continually respond to cellular stress. Recent studies have demonstrated that mitochondrial stress is relayed from mitochondria to the cytosol by the release of a proteolytic fragment of DELE1 that binds to the eIF2α kinase HRI to initiate integrated stress response (ISR) signaling. We report the cryo-electron microscopy structure of the C-terminal cleavage product of human DELE1, which assembles into a high-order oligomer. The oligomer consists of eight DELE1 monomers that assemble with D symmetry via two sets of hydrophobic inter-subunit interactions. We identified the key residues involved in DELE1 oligomerization, and confirmed their role in stabilizing the octamer in vitro and in cells using mutagenesis. We further show that assembly-impaired DELE1 mutants are compromised in their ability to induce HRI-dependent ISR activation in cell culture models. Together, our findings provide molecular insights into the activity of DELE1 and how it signals to promote ISR activity following mitochondrial insult.
History
DepositionJun 11, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 14, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 9, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Aug 23, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.3Sep 20, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Maltodextrin-binding protein,DAP3-binding cell death enhancer 1 short form
B: Maltodextrin-binding protein,DAP3-binding cell death enhancer 1 short form
C: Maltodextrin-binding protein,DAP3-binding cell death enhancer 1 short form
D: Maltodextrin-binding protein,DAP3-binding cell death enhancer 1 short form
E: Maltodextrin-binding protein,DAP3-binding cell death enhancer 1 short form
F: Maltodextrin-binding protein,DAP3-binding cell death enhancer 1 short form
G: Maltodextrin-binding protein,DAP3-binding cell death enhancer 1 short form
H: Maltodextrin-binding protein,DAP3-binding cell death enhancer 1 short form


Theoretical massNumber of molelcules
Total (without water)586,7518
Polymers586,7518
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Maltodextrin-binding protein,DAP3-binding cell death enhancer 1 short form / DELE1(S) / S-DELE1


Mass: 73343.836 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Gene: malE, GUB92_19955, NCTC8450_00456, NCTC9775_03059, DELE1, DELE, KIAA0141
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: A0A376KDN7, UniProt: Q14154

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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: Oligomeric structure of human DELE1 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
Buffer solutionpH: 8
SpecimenConc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 3600 X / Calibrated magnification: 43478 X / Nominal defocus max: 1300 nm / Nominal defocus min: 700 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM software
IDNameCategory
2Leginonimage acquisition
4cryoSPARCCTF correction
7UCSF Chimeramodel fitting
9cryoSPARCinitial Euler assignment
12cryoSPARC3D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING ONLY
SymmetryPoint symmetry: D4 (2x4 fold dihedral)
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 92455 / Symmetry type: POINT
Atomic model buildingSpace: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00313344
ELECTRON MICROSCOPYf_angle_d0.717992
ELECTRON MICROSCOPYf_dihedral_angle_d4.7031888
ELECTRON MICROSCOPYf_chiral_restr0.0411880
ELECTRON MICROSCOPYf_plane_restr0.0052384

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