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- EMDB-41363: Cryo-EM structure of DDB1deltaB-DDA1-DCAF5 -

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Basic information

Entry
Database: EMDB / ID: EMD-41363
TitleCryo-EM structure of DDB1deltaB-DDA1-DCAF5
Map dataMain map
Sample
  • Complex: Complex of DDB1deltaB-DDA1-DCAF5
    • Protein or peptide: DNA damage-binding protein 1
    • Protein or peptide: DDB1- and CUL4-associated factor 5
    • Protein or peptide: DET1- and DDB1-associated protein 1
KeywordsE3 ligase / protein degradation / cryo-EM / WD40 / LIGASE
Function / homology
Function and homology information


negative regulation of fatty acid biosynthetic process / 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 ...negative regulation of fatty acid biosynthetic process / 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 / positive regulation of viral genome replication / positive regulation of gluconeogenesis / proteasomal protein catabolic process / Recognition of DNA damage by PCNA-containing replication complex / nucleotide-excision repair / DNA Damage Recognition in GG-NER / Dual Incision in GG-NER / regulation of circadian rhythm / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Wnt signaling pathway / Formation of Incision Complex in GG-NER / Dual incision in TC-NER / protein polyubiquitination / Gap-filling DNA repair synthesis and ligation in TC-NER / positive regulation of protein catabolic process / cellular response to UV / rhythmic process / protein-macromolecule adaptor activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / site of double-strand break / Neddylation / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / damaged DNA binding / chromosome, telomeric region / protein ubiquitination / DNA repair / apoptotic process / DNA damage response / protein-containing complex binding / nucleolus / negative regulation of apoptotic process / protein-containing complex / DNA binding / extracellular space / extracellular exosome / nucleoplasm / nucleus / cytoplasm
Similarity search - Function
DDB1- and CUL4-associated factor 8-like / 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 / Mono-functional DNA-alkylating methyl methanesulfonate N-term / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / CPSF A subunit region / WD domain, G-beta repeat / WD40 repeats ...DDB1- and CUL4-associated factor 8-like / 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 / Mono-functional DNA-alkylating methyl methanesulfonate N-term / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / CPSF A subunit region / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
DNA damage-binding protein 1 / DDB1- and CUL4-associated factor 5 / DET1- and DDB1-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.63 Å
AuthorsYue H / Hunkeler M / Roy Burman SS / Fischer ES
Funding support United States, 1 items
OrganizationGrant numberCountry
The Mark Foundation6331505 United States
CitationJournal: Nature / Year: 2024
Title: Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF.
Authors: Sandi Radko-Juettner / Hong Yue / Jacquelyn A Myers / Raymond D Carter / Alexis N Robertson / Priya Mittal / Zhexin Zhu / Baranda S Hansen / Katherine A Donovan / Moritz Hunkeler / Wojciech ...Authors: Sandi Radko-Juettner / Hong Yue / Jacquelyn A Myers / Raymond D Carter / Alexis N Robertson / Priya Mittal / Zhexin Zhu / Baranda S Hansen / Katherine A Donovan / Moritz Hunkeler / Wojciech Rosikiewicz / Zhiping Wu / Meghan G McReynolds / Shourya S Roy Burman / Anna M Schmoker / Nada Mageed / Scott A Brown / Robert J Mobley / Janet F Partridge / Elizabeth A Stewart / Shondra M Pruett-Miller / Behnam Nabet / Junmin Peng / Nathanael S Gray / Eric S Fischer / Charles W M Roberts /
Abstract: Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to ...Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project. We report that the little-studied gene DDB1-CUL4-associated factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 has a quality-control function for SWI/SNF complexes and promotes the degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind to target loci and restore SWI/SNF-mediated gene expression to levels that are sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality-control factors may effectively reverse the malignant state of some cancers driven by disruption of tumour suppressor complexes.
History
DepositionJul 26, 2023-
Header (metadata) releaseApr 3, 2024-
Map releaseApr 3, 2024-
UpdateApr 17, 2024-
Current statusApr 17, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41363.png

Downloads & links

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Map

FileDownload / File: emd_41363.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMain map
Voxel sizeX=Y=Z: 1.1 Å
Density
Contour LevelBy AUTHOR: 1.56
Minimum - Maximum-6.986462 - 9.605305
Average (Standard dev.)-0.00009647099 (±0.19270463)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 330.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_41363_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: main map postprocessed with deepEMhancer

Fileemd_41363_additional_1.map
Annotationmain map postprocessed with deepEMhancer
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: half map 2

Fileemd_41363_half_map_1.map
Annotationhalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: half map 1

Fileemd_41363_half_map_2.map
Annotationhalf map 1
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Sample components

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Entire : Complex of DDB1deltaB-DDA1-DCAF5

EntireName: Complex of DDB1deltaB-DDA1-DCAF5
Components
  • Complex: Complex of DDB1deltaB-DDA1-DCAF5
    • Protein or peptide: DNA damage-binding protein 1
    • Protein or peptide: DDB1- and CUL4-associated factor 5
    • Protein or peptide: DET1- and DDB1-associated protein 1

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Supramolecule #1: Complex of DDB1deltaB-DDA1-DCAF5

SupramoleculeName: Complex of DDB1deltaB-DDA1-DCAF5 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 220 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: 96.425586 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGSSHHHHHH SAAHIVMVDA YKPTKGGRMS YNYVVTAQKP TAVNGCVTGH FTSAEDLNLL IAKNTRLEIY VVTAEGLRPV KEVGMYGKI AVMELFRPKG ESKDLLFILT AKYNACILEY KQSGESIDII TRAHGNVQDR IGRPSETGII GIIDPECRMI G LRLYDGLF ...String:
MGSSHHHHHH SAAHIVMVDA YKPTKGGRMS YNYVVTAQKP TAVNGCVTGH FTSAEDLNLL IAKNTRLEIY VVTAEGLRPV KEVGMYGKI AVMELFRPKG ESKDLLFILT AKYNACILEY KQSGESIDII TRAHGNVQDR IGRPSETGII GIIDPECRMI G LRLYDGLF KVIPLDRDNK ELKAFNIRLE ELHVIDVKFL YGCQAPTICF VYQDPQGRHV KTYEVSLREK EFNKGPWKQE NV EAEASMV IAVPEPFGGA IIIGQESITY HNGDKYLAIA PPIIKQSTIV CHNRVDPNGS RYLLGDMEGR LFMLLLEKEE QMD GTVTLK DLRVELLGET SIAECLTYLD NGVVFVGSRL GDSQLVKLNV DSNEQGSYVV AMETFTNLGP IVDMCVVDLE RQGQ GQLVT CSGAFKEGSL RIIRNGIGGN GNSGEIQKLH IRTVPLYESP RKICYQEVSQ CFGVLSSRIE VQDTSGGTTA LRPSA STQA LSSSVSSSKL FSSSTAPHET SFGEEVEVHN LLIIDQHTFE VLHAHQFLQN EYALSLVSCK LGKDPNTYFI VGTAMV YPE EAEPKQGRIV VFQYSDGKLQ TVAEKEVKGA VYSMVEFNGK LLASINSTVR LYEWTTEKEL RTECNHYNNI MALYLKT KG DFILVGDLMR SVLLLAYKPM EGNFEEIARD FNPNWMSAVE ILDDDNFLGA ENAFNLFVCQ KDSAATTDEE RQHLQEVG L FHLGEFVNVF CHGSLVMQNL GETSTPTQGS VLFGTVNGMI GLVTSLSESW YNLLLDMQNR LNKVIKSVGK IEHSFWRSF HTERKTEPAT GFIDGDLIES FLDISRPKMQ EVVANLQYDD GSGMKREATA DDLIKVVEEL TRIH

UniProtKB: DNA damage-binding protein 1, DNA damage-binding protein 1

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Macromolecule #2: DDB1- and CUL4-associated factor 5

MacromoleculeName: DDB1- and CUL4-associated factor 5 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 108.948688 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MDWSHPQFEK SAVGLNDIFE AQKIEWHEGG GGSGENLYFQ GGGRMKRRAG LGGSMRSVVG FLSQRGLHGD PLLTQDFQRR RLRGCRNLY KKDLLGHFGC VNAIEFSNNG GQWLVSGGDD RRVLLWHMEQ AIHSRVKPIQ LKGEHHSNIF CLAFNSGNTK V FSGGNDEQ ...String:
MDWSHPQFEK SAVGLNDIFE AQKIEWHEGG GGSGENLYFQ GGGRMKRRAG LGGSMRSVVG FLSQRGLHGD PLLTQDFQRR RLRGCRNLY KKDLLGHFGC VNAIEFSNNG GQWLVSGGDD RRVLLWHMEQ AIHSRVKPIQ LKGEHHSNIF CLAFNSGNTK V FSGGNDEQ VILHDVESSE TLDVFAHEDA VYGLSVSPVN DNIFASSSDD GRVLIWDIRE SPHGEPFCLA NYPSAFHSVM FN PVEPRLL ATANSKEGVG LWDIRKPQSS LLRYGGNLSL QSAMSVRFNS NGTQLLALRR RLPPVLYDIH SRLPVFQFDN QGY FNSCTM KSCCFAGDRD QYILSGSDDF NLYMWRIPAD PEAGGIGRVV NGAFMVLKGH RSIVNQVRFN PHTYMICSSG VEKI IKIWS PYKQPGCTGD LDGRIEDDSR CLYTHEEYIS LVLNSGSGLS HDYANQSVQE DPRMMAFFDS LVRREIEGWS SDSDS DLSE STILQLHAGV SERSGYTDSE SSASLPRSPP PTVDESADNA FHLGPLRVTT TNTVASTPPT PTCEDAASRQ QRLSAL RRY QDKRLLALSN ESDSEENVCE VELDTDLFPR PRSPSPEDES SSSSSSSSSE DEEELNERRA STWQRNAMRR RQKTTRE DK PSAPIKPTNT YIGEDNYDYP QIKVDDLSSS PTSSPERSTS TLEIQPSRAS PTSDIESVER KIYKAYKWLR YSYISYSN N KDGETSLVTG EADEGRAGTS HKDNPAPSSS KEACLNIAMA QRNQDLPPEG CSKDTFKEET PRTPSNGPGH EHSSHAWAE VPEGTSQDTG NSGSVEHPFE TKKLNGKALS SRAEEPPSPP VPKASGSTLN SGSGNCPRTQ SDDSEERSLE TICANHNNGR LHPRPPHPH NNGQNLGELE VVAYSSPGHS DTDRDNSSLT GTLLHKDCCG SEMACETPNA GTREDPTDTP ATDSSRAVHG H SGLKRQRI ELEDTDSENS SSEKKLKT

UniProtKB: DDB1- and CUL4-associated factor 5

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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: 14.542154 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MGSSHHHHHH SAVDENLYFQ GGGRMADFLK GLPVYNKSNF SRFHADSVCK ASNRRPSVYL PTREYPSEQI IVTEKTNILL RYLHQQWDK KNAAKKRDQE QVELEGESSA PPRKVARTDS PDMHEDT

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

Concentration0.9 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
200.0 mMNaClSodium chloridesodium chloride
25.0 mMHEPES2-[4-(2-Hydroxyethyl)piperazin-1-yl]ethane-1-sulfonic acid

Details: 25mM HEPES, pH 7.4, 200mM NaCl, 4mM TCEP
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Support film - Film thickness: 12 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 3.9e-05 kPa
VitrificationCryogen name: NITROGEN / Chamber humidity: 90 % / Chamber temperature: 283 K / Instrument: LEICA EM GP

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm / Nominal magnification: 36000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 1072 / Average exposure time: 4.494 sec. / Average electron dose: 53.349 e/Å2 / Details: 50 frames per movie
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1404938
Startup modelType of model: OTHER / Details: ab initio in cryoSPARC
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. v3.2) / Details: cryoSPARC
Final 3D classificationNumber classes: 6 / Avg.num./class: 230000 / Software - Name: cryoSPARC (ver. v3.2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. v3.2)
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.63 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v4.1.2) / Number images used: 547805
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

6q0r

chain_id: A, source_name: PDB, initial_model_type: experimental model

6q0r

chain_id: E, source_name: PDB, initial_model_type: experimental model
chain_id: B, source_name: RoseTTAFold, initial_model_type: in silico model
RefinementSpace: REAL / Protocol: OTHER / Overall B value: 97
Output model

PDB-8tl6:
Cryo-EM structure of DDB1deltaB-DDA1-DCAF5

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