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- EMDB-49974: Focused refinement of FBXO42-CCDC6-PP2Ac degradasome PP2Ac repeat4 -

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Basic information

Entry
Database: EMDB / ID: EMD-49974
TitleFocused refinement of FBXO42-CCDC6-PP2Ac degradasome PP2Ac repeat4
Map data
Sample
  • Complex: Complex of FBXO42-CCDC6-PP2Ac
KeywordsE3 ligase / phosphatase / scaffolding / TRANSFERASE
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.6 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_49974.png

Downloads & links

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Map

FileDownload / File: emd_49974.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 480 pix.
= 402.24 Å		0.84 Å/pix.
x 480 pix.
= 402.24 Å		0.84 Å/pix.
x 480 pix.
= 402.24 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.838 Å
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Contour LevelBy AUTHOR: 0.03
Minimum - Maximum-0.081135355 - 0.23008107
Average (Standard dev.)-0.00009919282 (±0.0029194152)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 402.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_49974_msk_1.map
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Half map: #2

Fileemd_49974_half_map_1.map
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Half map: #1

Fileemd_49974_half_map_2.map
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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

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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-#4
Source (natural)Organism: Homo sapiens (human)

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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: UltrAuFoil R1.2/1.3 / Support film - Material: GOLD / Support film - topology: HOLEY
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: 6.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 155244
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

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