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- PDB-8wqr: Structure of the DDB1-AMBRA1 E3 ligase receptor complex linked to... -

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Basic information

Entry
Database: PDB / ID: 8wqr
TitleStructure of the DDB1-AMBRA1 E3 ligase receptor complex linked to cell cycle regulation
Components
  • Activating molecule in BECN1-regulated autophagy protein 1
  • DNA damage-binding protein 1
KeywordsSTRUCTURAL PROTEIN / E3 ligase
Function / homology
Function and homology information


positive regulation of free ubiquitin chain polymerization / : / response to mitochondrial depolarisation / positive regulation of mitophagy / autophagy of mitochondrion / positive regulation by virus of viral protein levels in host cell / epigenetic programming in the zygotic pronuclei / spindle assembly involved in female meiosis / positive regulation of regulatory T cell differentiation / Cul4-RING E3 ubiquitin ligase complex ...positive regulation of free ubiquitin chain polymerization / : / response to mitochondrial depolarisation / positive regulation of mitophagy / autophagy of mitochondrion / positive regulation by virus of viral protein levels in host cell / epigenetic programming in the zygotic pronuclei / spindle assembly involved in female meiosis / positive regulation of regulatory T cell differentiation / Cul4-RING E3 ubiquitin ligase complex / UV-damage excision repair / biological process involved in interaction with symbiont / neural tube development / WD40-repeat domain binding / regulation of mitotic cell cycle phase transition / Cul4A-RING E3 ubiquitin ligase complex / negative regulation of cardiac muscle cell apoptotic process / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / Macroautophagy / negative regulation of reproductive process / negative regulation of developmental process / regulation of G1/S transition of mitotic cell cycle / axoneme / cullin family protein binding / mitophagy / ubiquitin-like ligase-substrate adaptor activity / autophagosome assembly / viral release from host cell / autophagosome / ectopic germ cell programmed cell death / proteasomal protein catabolic process / positive regulation of viral genome replication / positive regulation of autophagy / positive regulation of protein dephosphorylation / positive regulation of gluconeogenesis / cellular response to starvation / phagocytic vesicle / nucleotide-excision repair / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage Recognition in GG-NER / regulation of circadian rhythm / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Wnt signaling pathway / autophagy / 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 / GTPase binding / protein-macromolecule adaptor activity / Neddylation / site of double-strand break / ubiquitin-dependent protein catabolic process / protein phosphatase binding / proteasome-mediated ubiquitin-dependent protein catabolic process / mitochondrial outer membrane / negative regulation of neuron apoptotic process / chromosome, telomeric region / damaged DNA binding / cell differentiation / cytoskeleton / protein ubiquitination / cell cycle / negative regulation of cell population proliferation / intracellular membrane-bounded organelle / DNA repair / focal adhesion / apoptotic process / ubiquitin protein ligase binding / DNA damage response / protein-containing complex binding / nucleolus / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / perinuclear region of cytoplasm / endoplasmic reticulum / protein-containing complex / mitochondrion / DNA binding / extracellular space / extracellular exosome / nucleoplasm / nucleus / cytoplasm / cytosol
Similarity search - Function
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 / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat ...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 / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
DNA damage-binding protein 1 / Activating molecule in BECN1-regulated autophagy protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.08 Å
AuthorsLiu, M. / Wang, Y. / Su, M.Y. / Stjepanovic, G.
Funding support China, 1items
OrganizationGrant numberCountry
Other government2022A1515010856 China
CitationJournal: Nat Commun / Year: 2023
Title: Structure of the DDB1-AMBRA1 E3 ligase receptor complex linked to cell cycle regulation.
Authors: Ming Liu / Yang Wang / Fei Teng / Xinyi Mai / Xi Wang / Ming-Yuan Su / Goran Stjepanovic /
Abstract: AMBRA1 is a tumor suppressor protein that functions as a substrate receptor of the ubiquitin conjugation system with roles in autophagy and the cell cycle regulatory network. The intrinsic disorder ...AMBRA1 is a tumor suppressor protein that functions as a substrate receptor of the ubiquitin conjugation system with roles in autophagy and the cell cycle regulatory network. The intrinsic disorder of AMBRA1 has thus far precluded its structural determination. To solve this problem, we analyzed the dynamics of AMBRA1 using hydrogen deuterium exchange mass spectrometry (HDX-MS). The HDX results indicated that AMBRA1 is a highly flexible protein and can be stabilized upon interaction with DDB1, the adaptor of the Cullin4A/B E3 ligase. Here, we present the cryo-EM structure of AMBRA1 in complex with DDB1 at 3.08 Å resolution. The structure shows that parts of the N- and C-terminal structural regions in AMBRA1 fold together into the highly dynamic WD40 domain and reveals how DDB1 engages with AMBRA1 to create a binding scaffold for substrate recruitment. The N-terminal helix-loop-helix motif and WD40 domain of AMBRA1 associate with the double-propeller fold of DDB1. We also demonstrate that DDB1 binding-defective AMBRA1 mutants prevent ubiquitination of the substrate Cyclin D1 in vitro and increase cell cycle progression. Together, these results provide structural insights into the AMBRA1-ubiquitin ligase complex and suggest a mechanism by which AMBRA1 acts as a hub involved in various physiological processes.
History
DepositionOct 12, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 20, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Activating molecule in BECN1-regulated autophagy protein 1
A: DNA damage-binding protein 1


Theoretical massNumber of molelcules
Total (without water)171,5942
Polymers171,5942
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Activating molecule in BECN1-regulated autophagy protein 1


Mass: 44496.871 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AMBRA1 / Production host: Homo sapiens (human) / References: UniProt: Q9C0C7
#2: 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: 127097.469 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: Homo sapiens (human) / References: UniProt: Q16531

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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: DDB1-AMBRA1 complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
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: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 58.96 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 780090 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0049829
ELECTRON MICROSCOPYf_angle_d0.68113414
ELECTRON MICROSCOPYf_dihedral_angle_d4.8261466
ELECTRON MICROSCOPYf_chiral_restr0.0471633
ELECTRON MICROSCOPYf_plane_restr0.0051736

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