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- PDB-9ivd: Cryo-EM structure of CyclinD1 bound AMBRA1-DDB1 -

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Basic information

Entry
Database: PDB / ID: 9ivd
TitleCryo-EM structure of CyclinD1 bound AMBRA1-DDB1
Components
  • Activating molecule in BECN1-regulated autophagy protein 1
  • DNA damage-binding protein 1
  • G1/S-specific cyclin-D1
KeywordsSIGNALING PROTEIN / E3 ligase
Function / homology
Function and homology information


positive regulation of free ubiquitin chain polymerization / cyclin D1-CDK4 complex / cyclin D1-CDK6 complex / re-entry into mitotic cell cycle / Drug-mediated inhibition of CDK4/CDK6 activity / RUNX3 regulates WNT signaling / positive regulation of mammary gland epithelial cell proliferation / response to mitochondrial depolarisation / response to leptin / positive regulation of mitophagy ...positive regulation of free ubiquitin chain polymerization / cyclin D1-CDK4 complex / cyclin D1-CDK6 complex / re-entry into mitotic cell cycle / Drug-mediated inhibition of CDK4/CDK6 activity / RUNX3 regulates WNT signaling / positive regulation of mammary gland epithelial cell proliferation / response to mitochondrial depolarisation / response to leptin / positive regulation of mitophagy / Transcriptional regulation by RUNX2 / Leydig cell differentiation / proline-rich region binding / cyclin-dependent protein serine/threonine kinase activator activity / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / Regulation of RUNX1 Expression and Activity / response to iron ion / epigenetic programming in the zygotic pronuclei / neural tube development / positive regulation of regulatory T cell differentiation / mammary gland epithelial cell proliferation / cyclin-dependent protein serine/threonine kinase regulator activity / response to UV-A / UV-damage excision repair / biological process involved in interaction with symbiont / response to vitamin E / regulation of mitotic cell cycle phase transition / WD40-repeat domain binding / Macroautophagy / response to corticosterone / PTK6 Regulates Cell Cycle / negative regulation of epithelial cell differentiation / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of reproductive process / negative regulation of developmental process / Transcriptional Regulation by VENTX / microtubule organizing center / negative regulation of cardiac muscle cell apoptotic process / regulation of G1/S transition of mitotic cell cycle / mammary gland alveolus development / viral release from host cell / protein phosphatase activator activity / RUNX3 regulates p14-ARF / response to magnesium ion / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / cullin family protein binding / bicellular tight junction / positive regulation of G2/M transition of mitotic cell cycle / response to X-ray / axoneme / ectopic germ cell programmed cell death / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / positive regulation of G1/S transition of mitotic cell cycle / fat cell differentiation / positive regulation of viral genome replication / autophagosome assembly / cyclin-dependent protein kinase holoenzyme complex / mitophagy / ubiquitin-like ligase-substrate adaptor activity / phagocytic vesicle / mitotic G1 DNA damage checkpoint signaling / lactation / endoplasmic reticulum unfolded protein response / transcription repressor complex / proteasomal protein catabolic process / liver regeneration / positive regulation of autophagy / autophagosome / positive regulation of gluconeogenesis / cellular response to starvation / protein serine/threonine kinase activator activity / nucleotide-excision repair / Ubiquitin-dependent degradation of Cyclin D / sperm end piece / G1/S transition of mitotic cell cycle / regulation of circadian rhythm / Recognition of DNA damage by PCNA-containing replication complex / response to calcium ion / response to estrogen / Pre-NOTCH Transcription and Translation / DNA Damage Recognition in GG-NER / Dual Incision in GG-NER / SCF(Skp2)-mediated degradation of p27/p21 / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / histone deacetylase binding / Formation of TC-NER Pre-Incision Complex / Wnt signaling pathway / RMTs methylate histone arginines / neuron differentiation / Formation of Incision Complex in GG-NER / protein polyubiquitination / Dual incision in TC-NER / Cyclin D associated events in G1 / Gap-filling DNA repair synthesis and ligation in TC-NER / positive regulation of protein catabolic process
Similarity search - Function
: / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / Cyclin, N-terminal / Cyclin, N-terminal domain / : ...: / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / Cyclin, N-terminal / Cyclin, N-terminal domain / : / 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 / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / WD domain, G-beta repeat / 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
G1/S-specific cyclin-D1 / 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: 3.55 Å
AuthorsWang, Y. / Liu, M. / Su, M.-Y. / Stjepanovic, G.
Funding support China, 1items
OrganizationGrant numberCountry
Other government2024A1515011683 China
CitationJournal: Sci Adv / Year: 2025
Title: Mechanism of D-type cyclin recognition by the AMBRA1 E3 ligase receptor.
Authors: Yang Wang / Ming Liu / Shan Wang / Xinyi Mai / Xi Wang / Fei Teng / Tianrui Lyu / Ming-Yuan Su / Goran Stjepanovic /
Abstract: AMBRA1 is a tumor suppressor protein that functions as a substrate receptor in the ubiquitin conjugation system and regulates the stability of D-type cyclins and cell proliferation. Here, we present ...AMBRA1 is a tumor suppressor protein that functions as a substrate receptor in the ubiquitin conjugation system and regulates the stability of D-type cyclins and cell proliferation. Here, we present the cryo-EM structure of cyclin D1-bound AMBRA1-DDB1 complex at 3.55-Å resolution. The structure reveals a substrate interaction surface on the AMBRA1 WD40 domain that specifically binds to the C-terminal region of D-type cyclins. This interaction is dependent on the phosphorylation of Thr residue in the C-terminal phosphodegron site of D-type cyclins. The phosphodegron motif folds into a turn-like conformation, followed by a 3 helix that promotes its assembly with AMBRA1. In addition, we show that AMBRA1 mutants, which are defective in cyclin D1 binding, lead to cyclin D1 accumulation and DNA damage. Understanding the AMBRA1-D-type cyclin structure enhances the knowledge of the molecular mechanisms that govern the cell cycle control and may lead to potential therapeutic approaches for cancers linked to abnormal cyclin D activity.
History
DepositionJul 23, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Apr 23, 2025Provider: repository / Type: Initial release
Revision 1.0Apr 23, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 23, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Apr 23, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Revision 1.1Jul 16, 2025Group: Data collection / Database references
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Revision 2.0Jul 16, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / EM metadata
Group: Data processing / Database references / Experimental summary
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
E: G1/S-specific cyclin-D1
B: Activating molecule in BECN1-regulated autophagy protein 1
A: DNA damage-binding protein 1


Theoretical massNumber of molelcules
Total (without water)205,4413
Polymers205,4413
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein G1/S-specific cyclin-D1 / B-cell lymphoma 1 protein / BCL-1 / BCL-1 oncogene / PRAD1 oncogene


Mass: 33847.090 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCND1, BCL1, PRAD1 / Production host: Homo sapiens (human) / References: UniProt: P24385
#2: Protein Activating molecule in BECN1-regulated autophagy protein 1 / DDB1- and CUL4-associated factor 3


Mass: 44496.871 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AMBRA1, DCAF3, KIAA1736 / Production host: Homo sapiens (human) / References: UniProt: Q9C0C7
#3: 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
Has ligand of interestY
Has protein modificationY

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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: Complex of AMBRA1-DDB1 bound to CyclinD1-CDK4 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.244 MDa / Experimental 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: 1.198 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.55 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1015935 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0048806
ELECTRON MICROSCOPYf_angle_d0.63811999
ELECTRON MICROSCOPYf_dihedral_angle_d5.5021237
ELECTRON MICROSCOPYf_chiral_restr0.0461424
ELECTRON MICROSCOPYf_plane_restr0.0051520

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