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- PDB-9o04: CryoEM structure of the FBXO42-CCDC6-PP2Ac degradasome -

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Basic information

Entry
Database: PDB / ID: 9o04
TitleCryoEM structure of the FBXO42-CCDC6-PP2Ac degradasome
Components
  • Coiled-coil domain-containing protein 6
  • F-box only protein 42
  • SKP1
  • Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
KeywordsTRANSFERASE / E3 ligase / phosphatase / scaffolding
Function / homology
Function and homology information


PP2A-mediated dephosphorylation of key metabolic factors / RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity / peptidyl-threonine dephosphorylation / MASTL Facilitates Mitotic Progression / protein phosphatase type 2A complex / INTAC complex / RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity / FAR/SIN/STRIPAK complex / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism ...PP2A-mediated dephosphorylation of key metabolic factors / RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity / peptidyl-threonine dephosphorylation / MASTL Facilitates Mitotic Progression / protein phosphatase type 2A complex / INTAC complex / RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity / FAR/SIN/STRIPAK complex / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / Inhibition of replication initiation of damaged DNA by RB1/E2F1 / GABA receptor binding / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / ERKs are inactivated / Initiation of Nuclear Envelope (NE) Reformation / Beta-catenin phosphorylation cascade / Signaling by GSK3beta mutants / CTNNB1 S33 mutants aren't phosphorylated / CTNNB1 S37 mutants aren't phosphorylated / CTNNB1 S45 mutants aren't phosphorylated / CTNNB1 T41 mutants aren't phosphorylated / Co-stimulation by CD28 / regulation of growth / RNA polymerase II transcription initiation surveillance / Disassembly of the destruction complex and recruitment of AXIN to the membrane / protein dephosphorylation / negative regulation of epithelial to mesenchymal transition / Co-inhibition by CTLA4 / Platelet sensitization by LDL / SCF ubiquitin ligase complex / protein-serine/threonine phosphatase / ERK/MAPK targets / negative regulation of glycolytic process through fructose-6-phosphate / mesoderm development / vascular endothelial cell response to oscillatory fluid shear stress / protein serine/threonine phosphatase activity / positive regulation of NLRP3 inflammasome complex assembly / T cell homeostasis / regulation of cell differentiation / regulation of microtubule polymerization / regulation of G1/S transition of mitotic cell cycle / chromosome, centromeric region / DARPP-32 events / negative regulation of hippo signaling / Cyclin A/B1/B2 associated events during G2/M transition / ubiquitin-like ligase-substrate adaptor activity / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / phosphoprotein phosphatase activity / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / protein tyrosine phosphatase activity / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / Resolution of Sister Chromatid Cohesion / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / meiotic cell cycle / RAF activation / RHO GTPases Activate Formins / negative regulation of canonical Wnt signaling pathway / Spry regulation of FGF signaling / PKR-mediated signaling / SH3 domain binding / structural constituent of cytoskeleton / response to lead ion / Degradation of beta-catenin by the destruction complex / tau protein binding / spindle pole / Cyclin D associated events in G1 / Negative regulation of MAPK pathway / Separation of Sister Chromatids / Regulation of TP53 Degradation / mitotic cell cycle / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / microtubule cytoskeleton / cytoskeleton / intracellular signal transduction / membrane raft / protein heterodimerization activity / synapse / chromatin / mitochondrion / extracellular exosome / membrane / metal ion binding / identical protein binding / nucleus / plasma membrane / cytosol
Similarity search - Function
: / Protein of unknown function DUF2046 / Uncharacterized conserved protein H4 (DUF2046) / FBX42, beta-propeller domain / : / A Receptor for Ubiquitination Targets / F-box domain profile. / F-box-like / F-box-like domain superfamily / F-box domain ...: / Protein of unknown function DUF2046 / Uncharacterized conserved protein H4 (DUF2046) / FBX42, beta-propeller domain / : / A Receptor for Ubiquitination Targets / F-box domain profile. / F-box-like / F-box-like domain superfamily / F-box domain / Serine/threonine specific protein phosphatases signature. / Protein phosphatase 2A homologues, catalytic domain. / Serine/threonine-specific protein phosphatase/bis(5-nucleosyl)-tetraphosphatase / Kelch-type beta propeller / Calcineurin-like phosphoesterase domain, ApaH type / Calcineurin-like phosphoesterase / Metallo-dependent phosphatase-like
Similarity search - Domain/homology
: / Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform / Coiled-coil domain-containing protein 6 / F-box only protein 42
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsHsu, P.L. / Michaelian, N. / Azumaya, C. / Coassolo, S. / Yauch, R.L.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Nature / Year: 2026
Title: Template-driven scaffolding of SCF regulates PP2A degradation.
Authors: Sebastien Coassolo / Nairie Michaelian / Timurs Maculins / Caleigh M Azumaya / Tommy K Cheung / Jianping Yin / Inna Zilberleyb / Kanika Bajaj Pahuja / Thomas Garner / Ted Lau / Davis Mau / ...Authors: Sebastien Coassolo / Nairie Michaelian / Timurs Maculins / Caleigh M Azumaya / Tommy K Cheung / Jianping Yin / Inna Zilberleyb / Kanika Bajaj Pahuja / Thomas Garner / Ted Lau / Davis Mau / Matthew Grimmer / Jean-Philippe Fortin / Mike Costa / Yoana N Dimitrova / Christopher M Rose / Peter L Hsu / Robert L Yauch /
Abstract: Protein phosphatase 2A (PP2A) is a Ser/Thr phosphatase that regulates the phosphorylation of almost all cellular processes, including cell division and proliferation. PP2A forms heterotrimeric ...Protein phosphatase 2A (PP2A) is a Ser/Thr phosphatase that regulates the phosphorylation of almost all cellular processes, including cell division and proliferation. PP2A forms heterotrimeric holoenzyme complexes comprising a catalytic subunit (PP2Ac), a scaffolding subunit (PP2Aa) and variable B regulatory subunits that exert precise control over enzyme substrate specificity and prevent indiscriminate dephosphorylation of phosphoproteins. However, the mechanisms that control the activity of uncomplexed catalytic subunits have remained relatively unclear. Here we find that the E3 ligase SKP1-CUL1-F-box (SCF) complex containing F-box other protein 42 (FBXO42, also known as JFK; hereafter, SCF) degrades holoenzyme-free PP2Ac in a complex with the coiled-coil protein CCDC6 to maintain cancer cell fitness. The cryo-electron microscopy structure of the FBXO42-CCDC6-PP2Ac assembly reveals a pseudosymmetric architecture in which CCDC6 forms a central dimeric template that recruits multiple copies of PP2Ac and creates a substrate for FBXO42. Both the quaternary structure of this CCDC6-PP2Ac heterodimer and the post-translationally methylated tail of PP2Ac are recognized by FBXO42 for ubiquitination. The multivalent structure facilitated by CCDC6 enables the assembly of multiple degradation complexes along a single coiled coil, leading to the turnover of free phosphatases and downregulation of catalytic activity. Together, our findings define a mechanism for PP2A control through the ubiquitin-proteosome system and establish a paradigm for cullin-RING ligase-substrate interactions.
History
DepositionApr 2, 2025Deposition site: RCSB / Processing site: RCSB
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Coiled-coil domain-containing protein 6
B: Coiled-coil domain-containing protein 6
C: F-box only protein 42
D: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
E: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
F: SKP1
G: F-box only protein 42
H: SKP1
I: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
J: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
K: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
L: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
M: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
N: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)606,64130
Polymers605,76214
Non-polymers87916
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 Coiled-coil domain-containing protein 6 / Papillary thyroid carcinoma-encoded protein / Protein H4


Mass: 55322.977 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCDC6, D10S170, TST1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q16204
#2: Protein F-box only protein 42 / Just one F-box and Kelch domain-containing protein


Mass: 75126.867 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FBXO42, FBX42, JFK, KIAA1332 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q6P3S6
#3: Protein
Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform / PP2A-alpha / Replication protein C / RP-C


Mass: 38858.492 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPP2CA / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P67775, protein-serine/threonine phosphatase
#4: Protein SKP1


Mass: 16997.295 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Trichoplusia ni (cabbage looper)
#5: Chemical
ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: Mn
Has ligand of interestN
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 FBXO42-CCDC6-PP2Ac / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.5 / Details: 20 mM HEPES pH 7.5, 200 mM NaCl, 1 mM TCEP pH 7.5
SpecimenConc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: coated with self assembled monolayers / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 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 magnification: 105000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 2 sec. / Electron dose: 45 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 21534 / Details: 15.8 eps collected as 40 frame movies
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2SerialEMimage acquisition
4cryoSPARCCTF correction
9PHENIX1.20.1_4487model refinement
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 7261626
Details: template picked from 2D classes in Glacios screening dataset
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 155244 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
RefinementHighest resolution: 3.2 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00630047
ELECTRON MICROSCOPYf_angle_d1.35440723
ELECTRON MICROSCOPYf_dihedral_angle_d53991
ELECTRON MICROSCOPYf_chiral_restr0.0864362
ELECTRON MICROSCOPYf_plane_restr0.0115290

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