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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 / response to mitochondrial depolarisation / positive regulation of mitophagy / positive regulation of mammary gland epithelial cell proliferation / response to leptin ...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 / response to mitochondrial depolarisation / positive regulation of mitophagy / positive regulation of mammary gland epithelial cell proliferation / response to leptin / Transcriptional regulation by RUNX2 / Leydig cell differentiation / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / cyclin-dependent protein serine/threonine kinase activator activity / Cul4-RING E3 ubiquitin ligase complex / proline-rich region binding / UV-damage excision repair / Regulation of RUNX1 Expression and Activity / response to iron ion / neural tube development / positive regulation of regulatory T cell differentiation / biological process involved in interaction with symbiont / cyclin-dependent protein serine/threonine kinase regulator activity / negative regulation of cardiac muscle cell apoptotic process / regulation of mitotic cell cycle phase transition / mammary gland epithelial cell proliferation / response to UV-A / WD40-repeat domain binding / Cul4A-RING E3 ubiquitin ligase complex / response to corticosterone / response to vitamin E / negative regulation of epithelial cell differentiation / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / Macroautophagy / PTK6 Regulates Cell Cycle / fat cell differentiation / negative regulation of reproductive process / negative regulation of developmental process / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / microtubule organizing center / regulation of G1/S transition of mitotic cell cycle / response to magnesium ion / cullin family protein binding / viral release from host cell / protein phosphatase activator activity / Transcriptional Regulation by VENTX / RUNX3 regulates p14-ARF / axoneme / autophagosome assembly / mammary gland alveolus development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / response to X-ray / bicellular tight junction / ectopic germ cell programmed cell death / positive regulation of G1/S transition of mitotic cell cycle / ubiquitin-like ligase-substrate adaptor activity / positive regulation of viral genome replication / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / proteasomal protein catabolic process / endoplasmic reticulum unfolded protein response / cyclin-dependent protein kinase holoenzyme complex / mitophagy / phagocytic vesicle / lactation / mitotic G1 DNA damage checkpoint signaling / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of autophagy / positive regulation of gluconeogenesis / transcription repressor complex / Ubiquitin-dependent degradation of Cyclin D / autophagosome / cellular response to starvation / protein serine/threonine kinase activator activity / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage Recognition in GG-NER / nucleotide-excision repair / liver regeneration / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / G1/S transition of mitotic cell cycle / SCF(Skp2)-mediated degradation of p27/p21 / Formation of Incision Complex in GG-NER / regulation of circadian rhythm / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / Pre-NOTCH Transcription and Translation / Cyclin D associated events in G1 / RMTs methylate histone arginines / response to estrogen / histone deacetylase binding / Wnt signaling pathway / response to calcium ion / protein polyubiquitination / neuron differentiation / positive regulation of protein catabolic process / transcription corepressor activity
Similarity search - Function
: / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / RSE1/DDB1/CPSF1 second beta-propeller / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / Cleavage/polyadenylation specificity factor, A subunit, N-terminal ...: / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / 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, N-terminal / Cyclin, N-terminal domain / 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
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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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