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- EMDB-27269: Cryo-EM structure of human DELE1 in oligomeric form -

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Basic information

Entry
Database: EMDB / ID: EMD-27269
TitleCryo-EM structure of human DELE1 in oligomeric form
Map data
Sample
  • Complex: Oligomeric structure of human DELE1
    • Protein or peptide: Maltodextrin-binding protein,DAP3-binding cell death enhancer 1 short form
KeywordsOligomer / Mitochondria / Integrated Stress Response / Kinase / Tetratricopeptide repeat / PROTEIN BINDING
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsYang J / Lander GC
Funding support United States, 1 items
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, 2022-
Header (metadata) releaseJun 14, 2023-
Map releaseJun 14, 2023-
UpdateSep 20, 2023-
Current statusSep 20, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

Downloads & links

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Map

FileDownload / File: emd_27269.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.15 Å
Density
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.0018919202 - 1.7632177
Average (Standard dev.)0.00125419 (±0.025020568)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 294.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_27269_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: #1

Fileemd_27269_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire : Oligomeric structure of human DELE1

EntireName: Oligomeric structure of human DELE1
Components
  • Complex: Oligomeric structure of human DELE1
    • Protein or peptide: Maltodextrin-binding protein,DAP3-binding cell death enhancer 1 short form

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Supramolecule #1: Oligomeric structure of human DELE1

SupramoleculeName: Oligomeric structure of human DELE1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Maltodextrin-binding protein,DAP3-binding cell death enhancer 1 s...

MacromoleculeName: Maltodextrin-binding protein,DAP3-binding cell death enhancer 1 short form
type: protein_or_peptide / ID: 1 / Number of copies: 8 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 73.343836 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString: MKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFPQ VAATGDGPDI IFWAHDRFGG YAQSGLLAEI TPAAAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN KDLLPNPPKT WEEIPALDKE LKAKGKSALM FNLQEPYFTW P LIAADGGY ...String:
MKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFPQ VAATGDGPDI IFWAHDRFGG YAQSGLLAEI TPAAAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN KDLLPNPPKT WEEIPALDKE LKAKGKSALM FNLQEPYFTW P LIAADGGY AFKYAAGKYD IKDVGVDNAG AKAGLTFLVD LIKNKHMNAD TDYSIAEAAF NKGETAMTIN GPWAWSNIDT SA VNYGVTV LPTFKGQPSK PFVGVLSAGI NAASPNKELA KEFLENYLLT DEGLEAVNKD KPLGAVALKS YEEELAKDPR IAA TMENAQ KGEIMPNIPQ MSAFWYAVRT AVINAASGRQ TVDAALAAAQ TNAVDSKTLS LEEAVTSIQQ LFQLSVSIAF NFLG TENMK SGDHTAAFSY FQKAAARGYS KAQYNAGLCH EHGRGTPRDI SKAVLYYQLA ASQGHSLAQY RYARCLLRDP ASSWN PERQ RAVSLLKQAA DSGLREAQAF LGVLFTKEPY LDEQRAVKYL WLAANNGDSQ SRYHLGICYE KGLGVQRNLG EALRCY QQS AALGNEAAQE RLRALFSMGA AAPGPSDLTV TGLKSFSSPS LCSLNTLLAG TSRLPHASST GNLGLLCRSG HLGASLE AS SRAIPPHPYP LERSVVRLGF GSAAALEHHH HHH

UniProtKB: Maltodextrin-binding protein, DAP3-binding cell death enhancer 1

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration3.0 mg/mL
BufferpH: 8
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Calibrated magnification: 43478 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 1.3 µm / Nominal defocus min: 0.7000000000000001 µm / Nominal magnification: 3600
Sample stageCooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: D4 (2x4 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 92455
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL
Output model

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

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