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- EMDB-49992: CryoEM structure of the CCDC6-PP2Ac multimer -

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Basic information

Entry
Database: EMDB / ID: EMD-49992
TitleCryoEM structure of the CCDC6-PP2Ac multimer
Map dataComposite structure of the CCDC6-PP2Ac multimer
Sample
  • Complex: Complex of FBXO42-CCDC6-PP2Ac
    • Protein or peptide: Coiled-coil domain-containing protein 6
    • Protein or peptide: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
  • Ligand: MANGANESE (II) ION
Keywordsphosphatase / scaffolding / coiled-coil / STRUCTURAL PROTEIN / STRUCTURAL PROTEIN-Hydrolase complex
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 / regulation of hippo signaling / 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 / regulation of hippo signaling / 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 / snRNA processing / regulation of growth / GABA receptor binding / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / regulation of transcription elongation by RNA polymerase II / ERKs are inactivated / T cell homeostasis / 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 / RNA polymerase II transcription initiation surveillance / Disassembly of the destruction complex and recruitment of AXIN to the membrane / protein dephosphorylation / negative regulation of glycolytic process through fructose-6-phosphate / negative regulation of epithelial to mesenchymal transition / Co-inhibition by CTLA4 / Platelet sensitization by LDL / protein-serine/threonine phosphatase / ERK/MAPK targets / vascular endothelial cell response to oscillatory fluid shear stress / protein serine/threonine phosphatase activity / regulation of cell differentiation / positive regulation of NLRP3 inflammasome complex assembly / regulation of microtubule polymerization / DARPP-32 events / chromosome, centromeric region / negative regulation of hippo signaling / Cyclin A/B1/B2 associated events during G2/M transition / regulation of G1/S transition of mitotic cell cycle / 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 / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Resolution of Sister Chromatid Cohesion / negative regulation of canonical Wnt signaling pathway / RAF activation / RHO GTPases Activate Formins / meiotic cell cycle / Spry regulation of FGF signaling / SH3 domain binding / PKR-mediated signaling / response to lead ion / Degradation of beta-catenin by the destruction complex / tau protein binding / structural constituent of cytoskeleton / spindle pole / microtubule cytoskeleton / Cyclin D associated events in G1 / Negative regulation of MAPK pathway / Regulation of TP53 Degradation / Separation of Sister Chromatids / mitotic cell cycle / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / 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 / cytoplasm
Similarity search - Function
Protein of unknown function DUF2046 / Uncharacterized conserved protein H4 (DUF2046) / : / Serine/threonine specific protein phosphatases signature. / Protein phosphatase 2A homologues, catalytic domain. / Serine/threonine-specific protein phosphatase/bis(5-nucleosyl)-tetraphosphatase / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsHsu PL / Michaelian N / Azumaya C / Coassolo S / Yauch RL
Funding support1 items
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, 2025-
Header (metadata) releaseJan 21, 2026-
Map releaseJan 21, 2026-
UpdateAug 5, 2026-
Current statusAug 5, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_49992.png

Downloads & links

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Map

FileDownload / File: emd_49992.map.gz / Format: CCP4 / Size: 129.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationComposite structure of the CCDC6-PP2Ac multimer
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
1.24 Å/pix.
x 324 pix.
= 402.246 Å		1.24 Å/pix.
x 324 pix.
= 402.246 Å		1.24 Å/pix.
x 324 pix.
= 402.246 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.2415 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 6.5
Minimum - Maximum-44.071899999999999 - 74.746359999999996
Average (Standard dev.)0.0029746366 (±1.1165061)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions324324324
Spacing324324324
CellA=B=C: 402.246 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Complex of FBXO42-CCDC6-PP2Ac

EntireName: Complex of FBXO42-CCDC6-PP2Ac
Components
  • Complex: Complex of FBXO42-CCDC6-PP2Ac
    • Protein or peptide: Coiled-coil domain-containing protein 6
    • Protein or peptide: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
  • Ligand: MANGANESE (II) ION

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Supramolecule #1: Complex of FBXO42-CCDC6-PP2Ac

SupramoleculeName: Complex of FBXO42-CCDC6-PP2Ac / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Coiled-coil domain-containing protein 6

MacromoleculeName: Coiled-coil domain-containing protein 6 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 53.366883 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MADSASESDT DGAGGNSSSS AAMQSSCSST SGGGGGGGGG GGGGKSGGIV ISPFRLEELT NRLASLQQEN KVLKIELETY KLKCKALQE ENRDLRKASV TIQARAEQEE EFISNTLFKK IQALQKEKET LAVNYEKEEE FLTNELSRKL MQLQHEKAEL E QHLEQEQE ...String:
MADSASESDT DGAGGNSSSS AAMQSSCSST SGGGGGGGGG GGGGKSGGIV ISPFRLEELT NRLASLQQEN KVLKIELETY KLKCKALQE ENRDLRKASV TIQARAEQEE EFISNTLFKK IQALQKEKET LAVNYEKEEE FLTNELSRKL MQLQHEKAEL E QHLEQEQE FQVNKLMKKI KKLENDTISK QLTLEQLRRE KIDLENTLEQ EQEALVNRLW KRMDKLEAEK RILQEKLDQP VS APPSPRD ISMEIDSPEN MMRHIRFLKN EVERLKKQLR AAQLQHSEKM AQYLEEERHM REENLRLQRK LQREMERREA LCR QLSESE SSLEMDDERY FNEMSAQGLR PRTVSSPIPY TPSPSSSRPI SPGLSYASHT VGFTPPTSLT RAGMSYYNSP GLHV QHMGT SHGITRPSPR RSNSPDKFKR PTPPPSPNTQ TPVQPPPPPP PPPMQPTVPS AATSQPTPSQ HSAHPSSQP

UniProtKB: Coiled-coil domain-containing protein 6

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Macromolecule #2: Serine/threonine-protein phosphatase 2A catalytic subunit alpha i...

MacromoleculeName: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
type: protein_or_peptide / ID: 2 / Number of copies: 8 / Enantiomer: LEVO / EC number: protein-serine/threonine phosphatase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 35.636152 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MDEKVFTKEL DQWIEQLNEC KQLSESQVKS LCEKAKEILT KESNVQEVRC PVTVCGDVHG QFHDLMELFR IGGKSPDTNY LFMGDYVDR GYYSVETVTL LVALKVRYRE RITILRGNHE SRQITQVYGF YDECLRKYGN ANVWKYFTDL FDYLPLTALV D GQIFCLHG ...String:
MDEKVFTKEL DQWIEQLNEC KQLSESQVKS LCEKAKEILT KESNVQEVRC PVTVCGDVHG QFHDLMELFR IGGKSPDTNY LFMGDYVDR GYYSVETVTL LVALKVRYRE RITILRGNHE SRQITQVYGF YDECLRKYGN ANVWKYFTDL FDYLPLTALV D GQIFCLHG GLSPSIDTLD HIRALDRLQE VPHEGPMCDL LWSDPDDRGG WGISPRGAGY TFGQDISETF NHANGLTLVS RA HQLVMEG YNWCHDRNVV TIFSAPNYCY RCGNQAAIME LDDTLKYSFL QFDPAPRRGE PHVTRRTPDY FL

UniProtKB: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform

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Macromolecule #3: MANGANESE (II) ION

MacromoleculeName: MANGANESE (II) ION / type: ligand / ID: 3 / Number of copies: 16 / Formula: MN
Molecular weightTheoretical: 54.938 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.2 mg/mL
BufferpH: 7.5 / Details: 20 mM HEPES pH 7.5, 200 mM NaCl, 1 mM TCEP pH 7.5
GridModel: Quantifoil / Support film - Material: GOLD / Support film - topology: HOLEY / Support film - Film thickness: 2.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 21534 / Average exposure time: 2.0 sec. / Average electron dose: 45.0 e/Å2 / Details: 15.8 eps collected as 40 frame movies
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 7261626
Details: template picked from 2D classes in Glacios screening dataset
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE / Details: Ab initio starting model generation from dataset
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 215302
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC / Details: NU-refinement in cryoSPARC
Final 3D classificationNumber classes: 5 / Software - Name: cryoSPARC / Details: heterogeneous classification in cryoSPARC

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-9o0l:
CryoEM structure of the CCDC6-PP2Ac multimer

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