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- PDB-7okq: Cryo-EM Structure of the DDB1-DCAF1-CUL4A-RBX1 Complex -

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Basic information

Entry
Database: PDB / ID: 7okq
TitleCryo-EM Structure of the DDB1-DCAF1-CUL4A-RBX1 Complex
Components
  • Cullin-4A
  • DDB1- and CUL4-associated factor 1
  • DNA damage-binding protein 1
  • E3 ubiquitin-protein ligase RBX1
KeywordsLIGASE / ubiquitin / E3 / protein degradation
Function / homology
Function and homology information


cell competition in a multicellular organism / histone H2AT120 kinase activity / negative regulation of granulocyte differentiation / negative regulation of beige fat cell differentiation / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / V(D)J recombination / cullin-RING ubiquitin ligase complex / Cul7-RING ubiquitin ligase complex / regulation of DNA damage checkpoint ...cell competition in a multicellular organism / histone H2AT120 kinase activity / negative regulation of granulocyte differentiation / negative regulation of beige fat cell differentiation / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / V(D)J recombination / cullin-RING ubiquitin ligase complex / Cul7-RING ubiquitin ligase complex / regulation of DNA damage checkpoint / cellular response to chemical stress / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / protein K27-linked ubiquitination / positive regulation by virus of viral protein levels in host cell / positive regulation of protein autoubiquitination / regulation of nucleotide-excision repair / RNA polymerase II transcription initiation surveillance / protein neddylation / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / NEDD8 ligase activity / UV-damage excision repair / VCB complex / negative regulation of response to oxidative stress / Cul5-RING ubiquitin ligase complex / ubiquitin-ubiquitin ligase activity / SCF ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Cul2-RING ubiquitin ligase complex / negative regulation of type I interferon production / biological process involved in interaction with symbiont / WD40-repeat domain binding / regulation of mitotic cell cycle phase transition / Cul3-RING ubiquitin ligase complex / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / negative regulation of mitophagy / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / Prolactin receptor signaling / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of reproductive process / negative regulation of developmental process / hemopoiesis / viral release from host cell / somatic stem cell population maintenance / cullin family protein binding / protein monoubiquitination / positive regulation of G1/S transition of mitotic cell cycle / ectopic germ cell programmed cell death / positive regulation of viral genome replication / site of DNA damage / protein K48-linked ubiquitination / ubiquitin-like ligase-substrate adaptor activity / proteasomal protein catabolic process / signal transduction in response to DNA damage / Nuclear events stimulated by ALK signaling in cancer / transcription-coupled nucleotide-excision repair / regulation of cellular response to insulin stimulus / positive regulation of TORC1 signaling / negative regulation of insulin receptor signaling pathway / positive regulation of gluconeogenesis / post-translational protein modification / intrinsic apoptotic signaling pathway / B cell differentiation / sperm end piece / T cell activation / nuclear estrogen receptor binding / Regulation of BACH1 activity / negative regulation of canonical NF-kappaB signal transduction / nucleotide-excision repair / Degradation of CRY and PER proteins / cellular response to amino acid stimulus / Degradation of DVL / G1/S transition of mitotic cell cycle / Degradation of GLI1 by the proteasome / negative regulation of canonical Wnt signaling pathway / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Negative regulation of NOTCH4 signaling / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / Hedgehog 'on' state / Recognition of DNA damage by PCNA-containing replication complex / Vif-mediated degradation of APOBEC3G / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / regulation of circadian rhythm / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / RING-type E3 ubiquitin transferase / Degradation of beta-catenin by the destruction complex / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / DNA Damage Recognition in GG-NER / Evasion by RSV of host interferon responses / NOTCH1 Intracellular Domain Regulates Transcription / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Regulation of expression of SLITs and ROBOs / Wnt signaling pathway
Similarity search - Function
VPRBP/DCAF1 family / Lissencephaly type-1-like homology motif / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / LIS1 homology (LisH) motif profile. / LIS1 homology motif / Cullin protein neddylation domain / : / Cullin, conserved site / Cullin family signature. ...VPRBP/DCAF1 family / Lissencephaly type-1-like homology motif / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / LIS1 homology (LisH) motif profile. / LIS1 homology motif / Cullin protein neddylation domain / : / Cullin, conserved site / Cullin family signature. / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / Cullin, N-terminal / : / Cullin alpha solenoid domain / Cullin / Cullin homology domain / Cullin homology domain superfamily / Cullin family profile. / RSE1/DDB1/CPSF1 second beta-propeller / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / : / CPSF A subunit region / RSE1/DDB1/CPSF1 first beta-propeller / Zinc finger RING-type profile. / Zinc finger, RING-type / Armadillo-like helical / Armadillo-type fold / Zinc finger, RING/FYVE/PHD-type / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
E3 ubiquitin-protein ligase RBX1 / Cullin-4A / DNA damage-binding protein 1 / DDB1- and CUL4-associated factor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 8.4 Å
AuthorsMohamed, W.I. / Schenk, A.D. / Kempf, G. / Cavadini, S. / Thoma, N.H.
CitationJournal: EMBO J / Year: 2021
Title: The CRL4 cullin-RING ubiquitin ligase is activated following a switch in oligomerization state.
Authors: Weaam I Mohamed / Andreas D Schenk / Georg Kempf / Simone Cavadini / Anja Basters / Alessandro Potenza / Wassim Abdul Rahman / Julius Rabl / Kurt Reichermeier / Nicolas H Thomä /
Abstract: The cullin-4-based RING-type (CRL4) family of E3 ubiquitin ligases functions together with dedicated substrate receptors. Out of the ˜29 CRL4 substrate receptors reported, the DDB1- and CUL4- ...The cullin-4-based RING-type (CRL4) family of E3 ubiquitin ligases functions together with dedicated substrate receptors. Out of the ˜29 CRL4 substrate receptors reported, the DDB1- and CUL4-associated factor 1 (DCAF1) is essential for cellular survival and growth, and its deregulation has been implicated in tumorigenesis. We carried out biochemical and structural studies to examine the structure and mechanism of the CRL4 ligase. In the 8.4 Å cryo-EM map of CRL4 , four CUL4-RBX1-DDB1-DCAF1 protomers are organized into two dimeric sub-assemblies. In this arrangement, the WD40 domain of DCAF1 mediates binding with the cullin C-terminal domain (CTD) and the RBX1 subunit of a neighboring CRL4 protomer. This renders RBX1, the catalytic subunit of the ligase, inaccessible to the E2 ubiquitin-conjugating enzymes. Upon CRL4 activation by neddylation, the interaction between the cullin CTD and the neighboring DCAF1 protomer is broken, and the complex assumes an active dimeric conformation. Accordingly, a tetramerization-deficient CRL4 mutant has higher ubiquitin ligase activity compared to the wild-type. This study identifies a novel mechanism by which unneddylated and substrate-free CUL4 ligases can be maintained in an inactive state.
History
DepositionMay 18, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 13, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 24, 2021Group: 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 1.2Dec 1, 2021Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Jul 10, 2024Group: Data collection / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / em_admin / pdbx_initial_refinement_model / pdbx_struct_oper_list
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 / _pdbx_struct_oper_list.name / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

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Assembly

Deposited unit
A: DNA damage-binding protein 1
B: DDB1- and CUL4-associated factor 1
C: Cullin-4A
D: E3 ubiquitin-protein ligase RBX1
E: DNA damage-binding protein 1
F: DDB1- and CUL4-associated factor 1
G: Cullin-4A
H: E3 ubiquitin-protein ligase RBX1
I: DNA damage-binding protein 1
J: DDB1- and CUL4-associated factor 1
K: Cullin-4A
L: E3 ubiquitin-protein ligase RBX1
M: DNA damage-binding protein 1
N: DDB1- and CUL4-associated factor 1
O: Cullin-4A
P: E3 ubiquitin-protein ligase RBX1


Theoretical massNumber of molelcules
Total (without water)1,603,49616
Polymers1,603,49616
Non-polymers00
Water00
1
A: DNA damage-binding protein 1
B: DDB1- and CUL4-associated factor 1
C: Cullin-4A
D: E3 ubiquitin-protein ligase RBX1

E: DNA damage-binding protein 1
F: DDB1- and CUL4-associated factor 1
G: Cullin-4A
H: E3 ubiquitin-protein ligase RBX1

I: DNA damage-binding protein 1
J: DDB1- and CUL4-associated factor 1
K: Cullin-4A
L: E3 ubiquitin-protein ligase RBX1

M: DNA damage-binding protein 1
N: DDB1- and CUL4-associated factor 1
O: Cullin-4A
P: E3 ubiquitin-protein ligase RBX1


Theoretical massNumber of molelcules
Total (without water)1,603,49616
Polymers1,603,49616
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation3

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Components

#1: Protein
DNA damage-binding protein 1 / DDB p127 subunit / DNA damage-binding protein a / DDBa / Damage-specific DNA-binding protein 1 / ...DDB p127 subunit / DNA damage-binding protein a / DDBa / Damage-specific DNA-binding protein 1 / HBV X-associated protein 1 / XAP-1 / UV-damaged DNA-binding factor / UV-damaged DNA-binding protein 1 / UV-DDB 1 / XPE-binding factor / XPE-BF / Xeroderma pigmentosum group E-complementing protein / XPCe


Mass: 129394.898 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q16531
#2: Protein
DDB1- and CUL4-associated factor 1 / HIV-1 Vpr-binding protein / VprBP / Serine/threonine-protein kinase VPRBP / Vpr-interacting protein


Mass: 171279.094 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DCAF1, KIAA0800, RIP, VPRBP / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q9Y4B6, non-specific serine/threonine protein kinase
#3: Protein
Cullin-4A / CUL-4A


Mass: 86702.836 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CUL4A / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q13619
#4: Protein
E3 ubiquitin-protein ligase RBX1 / E3 ubiquitin-protein transferase RBX1 / Protein ZYP / RING finger protein 75 / RING-box protein 1 / ...E3 ubiquitin-protein transferase RBX1 / Protein ZYP / RING finger protein 75 / RING-box protein 1 / Rbx1 / Regulator of cullins 1 / ROC1


Mass: 13497.240 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RBX1, RNF75, ROC1 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P62877, RING-type E3 ubiquitin transferase, cullin-RING-type E3 NEDD8 transferase

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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: CRL4(DCAF1) / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
SpecimenEmbedding 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
Image recordingElectron dose: 45 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameCategory
7Cootmodel fitting
8UCSF Chimeramodel fitting
11RosettaEMmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 8.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 14000 / Symmetry type: POINT
Atomic model buildingB value: 596 / Protocol: FLEXIBLE FIT / Space: REAL / Target criteria: Real-space cross-correlation
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
12HYE

2hye

12HYE1PDBexperimental model
25JK7

5jk7

15JK72PDBexperimental model

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