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- PDB-9cb3: E2F1-Cyclin F Interface -

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Basic information

Entry
Database: PDB / ID: 9cb3
TitleE2F1-Cyclin F Interface
Components
  • Cyclin-F
  • E2F1 peptide
  • S-phase kinase-associated protein 1
KeywordsCELL CYCLE / SCF Ubiquitin Ligase
Function / homology
Function and homology information


negative regulation of centrosome duplication / negative regulation of fat cell proliferation / re-entry into mitotic cell cycle / Rb-E2F complex / lens fiber cell apoptotic process / F-box domain binding / Inhibition of replication initiation of damaged DNA by RB1/E2F1 / PcG protein complex / anaphase-promoting complex binding / positive regulation of ubiquitin protein ligase activity ...negative regulation of centrosome duplication / negative regulation of fat cell proliferation / re-entry into mitotic cell cycle / Rb-E2F complex / lens fiber cell apoptotic process / F-box domain binding / Inhibition of replication initiation of damaged DNA by RB1/E2F1 / PcG protein complex / anaphase-promoting complex binding / positive regulation of ubiquitin protein ligase activity / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / Cul7-RING ubiquitin ligase complex / maintenance of protein location in nucleus / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / mRNA stabilization / Transcription of E2F targets under negative control by DREAM complex / Activation of NOXA and translocation to mitochondria / anoikis / negative regulation of DNA binding / Activation of PUMA and translocation to mitochondria / cyclin-dependent protein serine/threonine kinase regulator activity / SCF ubiquitin ligase complex / DNA-binding transcription activator activity / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / ubiquitin ligase complex scaffold activity / negative regulation of fat cell differentiation / G2 Phase / Prolactin receptor signaling / G1/S-Specific Transcription / Transcriptional Regulation by E2F6 / regulation of G1/S transition of mitotic cell cycle / microtubule organizing center / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / cullin family protein binding / intrinsic apoptotic signaling pathway by p53 class mediator / protein monoubiquitination / cis-regulatory region sequence-specific DNA binding / ubiquitin-like ligase-substrate adaptor activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / protein K48-linked ubiquitination / Cyclin E associated events during G1/S transition / forebrain development / Cyclin A:Cdk2-associated events at S phase entry / Nuclear events stimulated by ALK signaling in cancer / cyclin-dependent protein kinase holoenzyme complex / centriole / Regulation of BACH1 activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / DNA damage checkpoint signaling / molecular function activator activity / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / Vpu mediated degradation of CD4 / Dectin-1 mediated noncanonical NF-kB signaling / placenta development / Activation of NF-kappaB in B cells / Degradation of GLI1 by the proteasome / Negative regulation of NOTCH4 signaling / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Iron uptake and transport / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / Degradation of beta-catenin by the destruction complex / beta-catenin binding / Oncogene Induced Senescence / NOTCH1 Intracellular Domain Regulates Transcription / Pre-NOTCH Transcription and Translation / CLEC7A (Dectin-1) signaling / SCF(Skp2)-mediated degradation of p27/p21 / FCERI mediated NF-kB activation / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / RNA polymerase II transcription regulator complex / G1/S transition of mitotic cell cycle / Interleukin-1 signaling / Transcriptional regulation of granulopoiesis / Orc1 removal from chromatin / positive regulation of fibroblast proliferation / intrinsic apoptotic signaling pathway in response to DNA damage / protein polyubiquitination / Regulation of RUNX2 expression and activity / Cyclin D associated events in G1 / sequence-specific double-stranded DNA binding / Regulation of PLK1 Activity at G2/M Transition / : / Antigen processing: Ubiquitination & Proteasome degradation / cell junction / Downstream TCR signaling / cellular response to xenobiotic stimulus / Neddylation / Oxidative Stress Induced Senescence / DNA-binding transcription factor binding / molecular adaptor activity / response to lipopolysaccharide / proteasome-mediated ubiquitin-dependent protein catabolic process / sequence-specific DNA binding / DNA-binding transcription factor activity, RNA polymerase II-specific / protein dimerization activity / regulation of cell cycle
Similarity search - Function
E2F transcription factor, CC-MB domain / E2F transcription factor CC-MB domain / E2F Family / E2F-DP heterodimerization region / E2F/DP family, winged-helix DNA-binding domain / E2F/DP family winged-helix DNA-binding domain / E2F/DP family winged-helix DNA-binding domain / A Receptor for Ubiquitination Targets / F-box domain profile. / F-box-like domain superfamily ...E2F transcription factor, CC-MB domain / E2F transcription factor CC-MB domain / E2F Family / E2F-DP heterodimerization region / E2F/DP family, winged-helix DNA-binding domain / E2F/DP family winged-helix DNA-binding domain / E2F/DP family winged-helix DNA-binding domain / A Receptor for Ubiquitination Targets / F-box domain profile. / F-box-like domain superfamily / F-box-like / SKP1 component, dimerisation / S-phase kinase-associated protein 1 / SKP1-like, dimerisation domain superfamily / Skp1 family, dimerisation domain / F-box domain / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / SKP1/BTB/POZ domain superfamily / Tetratricopeptide-like helical domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
Cyclin-F / S-phase kinase-associated protein 1 / Transcription factor E2F1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.47 Å
AuthorsNgoi, P. / Serrao, V.H. / Rubin, S.M.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)P01 CA254867 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM145255 United States
CitationJournal: bioRxiv / Year: 2025
Title: Structural mechanism for recognition of E2F1 by the ubiquitin ligase adaptor Cyclin F.
Authors: Peter Ngoi / Xianxi Wang / Sivasankar Putta / Ricardo F Da Luz / Vitor Hugo B Serrão / Michael J Emanuele / Seth M Rubin /
Abstract: Cyclin F, a non-canonical member of the cyclin protein family, plays a critical role in regulating the precise transitions of cell-cycle events. Unlike canonical cyclins, which bind and activate ...Cyclin F, a non-canonical member of the cyclin protein family, plays a critical role in regulating the precise transitions of cell-cycle events. Unlike canonical cyclins, which bind and activate cyclin-dependent kinases (CDKs), Cyclin F functions as a substrate receptor protein within the Skp1-Cullin-F box (SCF) E3 ubiquitin ligase complex, enabling the ubiquitylation of target proteins. The structural features that distinguish Cyclin F as a ligase adaptor and the mechanisms underlying its selective substrate recruitment over Cyclin A, which functions in complex with CDK2 at a similar time in the cell cycle, remain largely unexplored. We utilized single-particle cryo-electron microscopy to elucidate the structure of a Cyclin F-Skp1 complex bound to an E2F1 peptide. The structure and biochemical analysis reveal important differences in the substrate-binding site of Cyclin F compared to Cyclin A. Our findings expand on the canonical cyclin-binding motif (Cy or RxL) and highlight the importance of electrostatics at the E2F1 binding interface, which varies for Cyclin F and Cyclin A. Our results advance our understanding of E2F1 regulation and may inform the development of inhibitors targeting Cyclin F.
History
DepositionJun 18, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 12, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cyclin-F
B: S-phase kinase-associated protein 1
C: E2F1 peptide


Theoretical massNumber of molelcules
Total (without water)91,9173
Polymers91,9173
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 Cyclin-F / F-box only protein 1


Mass: 71695.984 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNF, FBX1, FBXO1 / Cell line (production host): IPLB-Sf-21-AE / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P41002
#2: Protein S-phase kinase-associated protein 1 / SKP1 / Cyclin-A/CDK2-associated protein p19 / p19A / Organ of Corti protein 2 / OCP-2 / Organ of ...SKP1 / Cyclin-A/CDK2-associated protein p19 / p19A / Organ of Corti protein 2 / OCP-2 / Organ of Corti protein II / OCP-II / RNA polymerase II elongation factor-like protein / SIII / Transcription elongation factor B polypeptide 1-like / p19skp1


Mass: 18679.965 Da / Num. of mol.: 1 / Fragment: BTB domain (UNP residues 7-128)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SKP1, EMC19, OCP2, SKP1A, TCEB1L / Cell line (production host): IPLB-Sf-21-AE / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63208
#3: Protein/peptide E2F1 peptide


Mass: 1540.810 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q01094
Has protein modificationN

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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: E2F1-CyclinF-Skp1 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.09176483 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
125 mMTrisC4H11NO31
2150 mMSodium ChlorideNaCl1
31 mMDithiothreitol(CH(OH)CH2SH)21
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 400 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 0.57 sec. / Electron dose: 45.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 7611

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.4.1particle selection
2SerialEM4.4image acquisition
4cryoSPARC4.4.1CTF correction
7Coot0.9.8model fitting
9PHENIX1.2model refinement
10cryoSPARC4.4.1initial Euler assignment
11cryoSPARC4.4.1final Euler assignment
12cryoSPARC4.4.1classification
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 7781999
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.47 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 103503 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingB value: 177 / Protocol: RIGID BODY FIT / Space: REAL
Atomic model building
ID 3D fitting-IDChain-IDSource nameType
11AAlphaFoldin silico model
21BAlphaFoldin silico model
31CAlphaFoldin silico model
RefinementCross valid method: NONE

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