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- EMDB-46867: The ternary complex of DDB1, DDA1, DET1 -

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Basic information

Entry
Database: EMDB / ID: EMD-46867
TitleThe ternary complex of DDB1, DDA1, DET1
Map dataprimary map
Sample
  • Complex: DDB1:DDA1:DET1
    • Protein or peptide: DNA damage-binding protein 1
    • Protein or peptide: DET1 homolog
    • Protein or peptide: DET1- and DDB1-associated protein 1
KeywordsE3 ubiquitin ligase system / complex / degradation / cul4-ring / PROTEIN BINDING
Function / homology
Function and homology information


cullin-RING ubiquitin ligase complex / positive regulation by virus of viral protein levels in host cell / epigenetic programming in the zygotic pronuclei / spindle assembly involved in female meiosis / Cul4-RING E3 ubiquitin ligase complex / UV-damage excision repair / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition / WD40-repeat domain binding / Cul4A-RING E3 ubiquitin ligase complex ...cullin-RING ubiquitin ligase complex / positive regulation by virus of viral protein levels in host cell / epigenetic programming in the zygotic pronuclei / spindle assembly involved in female meiosis / Cul4-RING E3 ubiquitin ligase complex / UV-damage excision repair / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition / WD40-repeat domain binding / Cul4A-RING E3 ubiquitin ligase complex / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of reproductive process / negative regulation of developmental process / cullin family protein binding / viral release from host cell / ectopic germ cell programmed cell death / ubiquitin-like ligase-substrate adaptor activity / positive regulation of viral genome replication / proteasomal protein catabolic process / positive regulation of gluconeogenesis / nucleotide-excision repair / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage Recognition in GG-NER / regulation of circadian rhythm / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Dual Incision in GG-NER / Formation of TC-NER Pre-Incision Complex / Wnt signaling pathway / Formation of Incision Complex in GG-NER / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / protein polyubiquitination / positive regulation of protein catabolic process / cellular response to UV / rhythmic process / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation / site of double-strand break / ubiquitin-dependent protein catabolic process / protein-containing complex assembly / protein-macromolecule adaptor activity / proteasome-mediated ubiquitin-dependent protein catabolic process / damaged DNA binding / chromosome, telomeric region / protein ubiquitination / DNA repair / ubiquitin protein ligase binding / DNA damage response / apoptotic process / protein-containing complex binding / negative regulation of apoptotic process / nucleolus / protein-containing complex / DNA binding / extracellular space / extracellular exosome / nucleoplasm / nucleus / cytoplasm
Similarity search - Function
De-etiolated protein 1, Det1 / De-etiolated protein 1 Det1 / DET1- and DDB1-associated protein 1, N-terminal / DET1- and DDB1-associated protein 1 / Det1 complexing ubiquitin ligase / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / RSE1/DDB1/CPSF1 first beta-propeller / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / : / CPSF A subunit region ...De-etiolated protein 1, Det1 / De-etiolated protein 1 Det1 / DET1- and DDB1-associated protein 1, N-terminal / DET1- and DDB1-associated protein 1 / Det1 complexing ubiquitin ligase / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / RSE1/DDB1/CPSF1 first beta-propeller / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / : / CPSF A subunit region / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
DNA damage-binding protein 1 / DET1 homolog / DET1- and DDB1-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsSchubert AF / Kschonsak M / Harris SF
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Impairment of DET1 causes neurological defects and lethality in mice and humans.
Authors: Ozge Karayel / Allison Soung / Hem Gurung / Alexander F Schubert / Susan Klaeger / Marc Kschonsak / Aljazi Al-Maraghi / Ajaz A Bhat / Ammira S Alshabeeb Akil / Debra L Dugger / Joshua D ...Authors: Ozge Karayel / Allison Soung / Hem Gurung / Alexander F Schubert / Susan Klaeger / Marc Kschonsak / Aljazi Al-Maraghi / Ajaz A Bhat / Ammira S Alshabeeb Akil / Debra L Dugger / Joshua D Webster / Dorothy M French / Dhullipala Anand / Naharmal Soni / Khalid A Fakhro / Christopher M Rose / Seth F Harris / Ada Ndoja / Kim Newton / Vishva M Dixit /
Abstract: COP1 and DET1 are components of an E3 ubiquitin ligase that is conserved from plants to humans. Mammalian COP1 binds to DET1 and is a substrate adaptor for the CUL4A-DDB1-RBX1 RING E3 ligase. ...COP1 and DET1 are components of an E3 ubiquitin ligase that is conserved from plants to humans. Mammalian COP1 binds to DET1 and is a substrate adaptor for the CUL4A-DDB1-RBX1 RING E3 ligase. Transcription factor substrates, including c-Jun, ETV4, and ETV5, are targeted for proteasomal degradation to effect rapid transcriptional changes in response to cues such as growth factor deprivation. Here, we link a homozygous mutation to lethal developmental abnormalities in humans. Experimental cryo-electron microscopy of the DET1 complex with DDB1 and DDA1, as well as co-immunoprecipitation experiments, revealed that DET1 impairs binding to DDB1, thereby compromising E3 ligase function. Accordingly, human-induced pluripotent stem cells homozygous for expressed ETV4 and ETV5 highly, and exhibited defective mitochondrial homeostasis and aberrant caspase-dependent cell death when differentiated into neurons. Neuronal cell death was increased further in the presence of -deficient microglia as compared to WT microglia, indicating that the deleterious effects of the p.R26W mutation may stem from the dysregulation of multiple cell types. Mice lacking died during embryogenesis, while deletion just in neural stem cells elicited hydrocephalus, cerebellar dysplasia, and neonatal lethality. Our findings highlight an important role for DET1 in the neurological development of mice and humans.
History
DepositionSep 3, 2024-
Header (metadata) releaseFeb 5, 2025-
Map releaseFeb 5, 2025-
UpdateMar 5, 2025-
Current statusMar 5, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46867.png

Downloads & links

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Map

FileDownload / File: emd_46867.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationprimary map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 480 pix.
= 395.52 Å		0.82 Å/pix.
x 480 pix.
= 395.52 Å		0.82 Å/pix.
x 480 pix.
= 395.52 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.824 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.05
Minimum - Maximum-0.1518419 - 0.2861895
Average (Standard dev.)-0.000063666645 (±0.0056726653)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 395.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_46867_msk_1.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: half map A

Fileemd_46867_half_map_1.map
Annotationhalf map A
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: half map B

Fileemd_46867_half_map_2.map
Annotationhalf map B
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : DDB1:DDA1:DET1

EntireName: DDB1:DDA1:DET1
Components
  • Complex: DDB1:DDA1:DET1
    • Protein or peptide: DNA damage-binding protein 1
    • Protein or peptide: DET1 homolog
    • Protein or peptide: DET1- and DDB1-associated protein 1

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Supramolecule #1: DDB1:DDA1:DET1

SupramoleculeName: DDB1:DDA1:DET1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all / Details: Ternary complex of DDB1, DDA1, and DET1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 205 KDa

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Macromolecule #1: DNA damage-binding protein 1

MacromoleculeName: DNA damage-binding protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 129.054492 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHHHHHG ENLYFQSYNY VVTAQKPTAV NGCVTGHFTS AEDLNLLIAK NTRLEIYVVT AEGLRPVKEV GMYGKIAVME LFRPKGESK DLLFILTAKY NACILEYKQS GESIDIITRA HGNVQDRIGR PSETGIIGII DPECRMIGLR LYDGLFKVIP L DRDNKELK ...String:
MHHHHHHHHG ENLYFQSYNY VVTAQKPTAV NGCVTGHFTS AEDLNLLIAK NTRLEIYVVT AEGLRPVKEV GMYGKIAVME LFRPKGESK DLLFILTAKY NACILEYKQS GESIDIITRA HGNVQDRIGR PSETGIIGII DPECRMIGLR LYDGLFKVIP L DRDNKELK AFNIRLEELH VIDVKFLYGC QAPTICFVYQ DPQGRHVKTY EVSLREKEFN KGPWKQENVE AEASMVIAVP EP FGGAIII GQESITYHNG DKYLAIAPPI IKQSTIVCHN RVDPNGSRYL LGDMEGRLFM LLLEKEEQMD GTVTLKDLRV ELL GETSIA ECLTYLDNGV VFVGSRLGDS QLVKLNVDSN EQGSYVVAME TFTNLGPIVD MCVVDLERQG QGQLVTCSGA FKEG SLRII RNGIGIHEHA SIDLPGIKGL WPLRSDPNRE TDDTLVLSFV GQTRVLMLNG EEVEETELMG FVDDQQTFFC GNVAH QQLI QITSASVRLV SQEPKALVSE WKEPQAKNIS VASCNSSQVV VAVGRALYYL QIHPQELRQI SHTEMEHEVA CLDITP LGD SNGLSPLCAI GLWTDISARI LKLPSFELLH KEMLGGEIIP RSILMTTFES SHYLLCALGD GALFYFGLNI ETGLLSD RK KVTLGTQPTV LRTFRSLSTT NVFACSDRPT VIYSSNHKLV FSNVNLKEVN YMCPLNSDGY PDSLALANNS TLTIGTID E IQKLHIRTVP LYESPRKICY QEVSQCFGVL SSRIEVQDTS GGTTALRPSA STQALSSSVS SSKLFSSSTA PHETSFGEE VEVHNLLIID QHTFEVLHAH QFLQNEYALS LVSCKLGKDP NTYFIVGTAM VYPEEAEPKQ GRIVVFQYSD GKLQTVAEKE VKGAVYSMV EFNGKLLASI NSTVRLYEWT TEKELRTECN HYNNIMALYL KTKGDFILVG DLMRSVLLLA YKPMEGNFEE I ARDFNPNW MSAVEILDDD NFLGAENAFN LFVCQKDSAA TTDEERQHLQ EVGLFHLGEF VNVFCHGSLV MQNLGETSTP TQ GSVLFGT VNGMIGLVTS LSESWYNLLL DMQNRLNKVI KSVGKIEHSF WRSFHTERKT EPATGFIDGD LIESFLDISR PKM QEVVAN LQYDDGSGMK REATADDLIK VVEELTRIH

UniProtKB: DNA damage-binding protein 1

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Macromolecule #2: DET1 homolog

MacromoleculeName: DET1 homolog / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 64.749027 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MDYKDDDDKG ENLYFQGSRI QNQNVIHRLE RRRISSGKAG THWHQVRVFH QNVFPNFTVV NVEKPPCFLR KFSPDGRYFI AFSSDQTSL EIYEYQGCQA AEDLLQGYEG EILSNGNDQR SVNIRGRLFE RFFVLLHITN VAANGEHLNR ECSLFTDDCR C VIVGSAAY ...String:
MDYKDDDDKG ENLYFQGSRI QNQNVIHRLE RRRISSGKAG THWHQVRVFH QNVFPNFTVV NVEKPPCFLR KFSPDGRYFI AFSSDQTSL EIYEYQGCQA AEDLLQGYEG EILSNGNDQR SVNIRGRLFE RFFVLLHITN VAANGEHLNR ECSLFTDDCR C VIVGSAAY LPDEPHPPFF EVYRNSESVT PNPRSPLEDY SLHIIDLHTG RLCDTRTFKC DKVVLSHNQG LYLYKNILAI LS VQQQTIH VFQVTPEGTF IDVRTIGRFC YEDDLLTVSA VFPEVQRDSQ TGMANPFRDP FINSLKHRLL VYLWRRAEQD GSA MAKRRF FQYFDQLRQL RMWKMQLLDE NHLFIKYTSE DVVTLRVTDP SQASFFVVYN MVTTEVIAVF ENTSDELLEL FENF CDLFR NATLHSEVQF PCSASSNNFA RQIQRRFKDT IINAKYGGHT EAVRRLLGQL PISAQSYSGS PYLDLSLFSY DDKWV SVME RPKTCGDHPI RFYARDSGLL KFEIQAGLLG RPINHTVRRL VAFTFHPFEP FAISVQRTNA EYVVNFHMRH CCT

UniProtKB: DET1 homolog

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Macromolecule #3: DET1- and DDB1-associated protein 1

MacromoleculeName: DET1- and DDB1-associated protein 1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.855297 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MADFLKGLPV YNKSNFSRFH ADSVCKASNR RPSVYLPTRE YPSEQIIVTE KTNILLRYLH QQWDKKNAAK KRDQEQVELE GESSAPPRK VARTDSPDMH EDT

UniProtKB: DET1- and DDB1-associated protein 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

Concentration0.5 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
200.0 mMNaClSodium Chloride
25.0 mMHEPES
1.0 mMtris(2-carboxyethyl)phosphine
GridModel: UltrAuFoil R0./1 / Material: GOLD / Mesh: 300
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Average exposure time: 0.25 sec. / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1805888
Startup modelType of model: OTHER / Details: Ab initio reconstruction
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 49212
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC

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