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- PDB-9n0y: PP2A-B55 Holoenzyme with Eya3 -

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Basic information

Entry
Database: PDB / ID: 9n0y
TitlePP2A-B55 Holoenzyme with Eya3
Components
  • Protein phosphatase EYA3
  • Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform
  • Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform
  • Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
KeywordsONCOPROTEIN / Ser/Thr phosphatase / complex / Myc stabilization
Function / homology
Function and homology information


histone H2AXY142 phosphatase activity / regulation of chromosome segregation / meiotic spindle elongation / 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 / regulation of meiotic cell cycle process involved in oocyte maturation / mitotic sister chromatid separation / MASTL Facilitates Mitotic Progression ...histone H2AXY142 phosphatase activity / regulation of chromosome segregation / meiotic spindle elongation / 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 / regulation of meiotic cell cycle process involved in oocyte maturation / mitotic sister chromatid separation / MASTL Facilitates Mitotic Progression / protein phosphatase type 2A complex / meiotic sister chromatid cohesion, centromeric / INTAC complex / female meiotic nuclear division / 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 / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / protein phosphatase regulator activity / protein antigen binding / 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 / regulation of growth / Co-stimulation by CD28 / RNA polymerase II transcription initiation surveillance / Disassembly of the destruction complex and recruitment of AXIN to the membrane / protein dephosphorylation / T cell homeostasis / negative regulation of epithelial to mesenchymal transition / Co-inhibition by CTLA4 / Platelet sensitization by LDL / protein-serine/threonine phosphatase / response to ionizing radiation / negative regulation of glycolytic process through fructose-6-phosphate / ERK/MAPK targets / vascular endothelial cell response to oscillatory fluid shear stress / mesoderm development / protein serine/threonine phosphatase activity / regulation of cell differentiation / positive regulation of NLRP3 inflammasome complex assembly / regulation of microtubule polymerization / lateral plasma membrane / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / DARPP-32 events / chromosome, centromeric region / anatomical structure morphogenesis / enzyme-substrate adaptor activity / 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) / spindle assembly / visual perception / phosphoprotein phosphatase activity / protein-tyrosine-phosphatase / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / Recruitment of mitotic centrosome proteins and complexes / protein tyrosine phosphatase activity / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / protein phosphatase 2A binding / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / AURKA Activation by TPX2 / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Resolution of Sister Chromatid Cohesion / positive regulation of DNA repair / chromosome segregation / negative regulation of canonical Wnt signaling pathway / RAF activation / RHO GTPases Activate Formins / meiotic cell cycle / Spry regulation of FGF signaling / PKR-mediated signaling / response to lead ion / tau protein binding / Degradation of beta-catenin by the destruction complex / spindle pole / Cyclin D associated events in G1 / Negative regulation of MAPK pathway / Regulation of TP53 Degradation / Separation of Sister Chromatids / microtubule cytoskeleton / Regulation of PLK1 Activity at G2/M Transition / double-strand break repair / mitotic cell cycle
Similarity search - Function
EYA domain / Eyes absent family / EYA domain superfamily / EYA domain, metazoan / Protein phosphatase 2A regulatory subunit PR55 / Protein phosphatase 2A regulatory subunit PR55, conserved site / Protein phosphatase 2A regulatory subunit PR55 signature 1. / Protein phosphatase 2A regulatory subunit PR55 signature 2. / : / : ...EYA domain / Eyes absent family / EYA domain superfamily / EYA domain, metazoan / Protein phosphatase 2A regulatory subunit PR55 / Protein phosphatase 2A regulatory subunit PR55, conserved site / Protein phosphatase 2A regulatory subunit PR55 signature 1. / Protein phosphatase 2A regulatory subunit PR55 signature 2. / : / : / : / PIK3R4-like, middle domain / HEAT repeat / HEAT repeat / : / PPP2R1A-like HEAT repeat / Serine/threonine specific protein phosphatases signature. / Protein phosphatase 2A homologues, catalytic domain. / Serine/threonine-specific protein phosphatase/bis(5-nucleosyl)-tetraphosphatase / HEAT, type 2 / HEAT repeat profile. / HEAT repeats / Calcineurin-like phosphoesterase domain, ApaH type / Calcineurin-like phosphoesterase / haloacid dehalogenase-like hydrolase / Metallo-dependent phosphatase-like / Armadillo-like helical / Armadillo-type fold / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform / Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform / Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform / Protein phosphatase EYA3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.71 Å
AuthorsShi, S. / Li, X. / Alderman, C. / Zhao, R.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM145289 United States
CitationJournal: J Biol Chem / Year: 2025
Title: Cryo-EM structures reveal the PP2A-B55α and Eya3 interaction that can be disrupted by a peptide inhibitor.
Authors: Shasha Shi / Xueni Li / Christopher Alderman / Lars Wick / Wei Huang / North Foulon / Lingdi Zhang / John Rossi / Wenxin Hu / Shouqing Cui / Hongjin Zheng / Derek J Taylor / Heide L Ford / Rui Zhao /
Abstract: We have previously shown that Eya3 recruits PP2A-B55α to dephosphorylate pT58 on Myc, increasing Myc stability and enhancing primary tumor growth of triple-negative breast cancer (TNBC). However, ...We have previously shown that Eya3 recruits PP2A-B55α to dephosphorylate pT58 on Myc, increasing Myc stability and enhancing primary tumor growth of triple-negative breast cancer (TNBC). However, the molecular details of how Eya3 recruits PP2A-B55α remain unclear. Here, we determined the cryo-EM structures of PP2A-B55α bound with Eya3, with an inhibitory peptide B55i, and in its unbound state. These studies demonstrate that Eya3 binds B55α through an extended peptide in the N-terminal domain of Eya3. The Eya3 peptide, PP2A-B55α substrates, and protein-peptide inhibitors including B55i bind to a similar area on the B55α surface, but the molecular details of the binding differ. We further demonstrated that the B55i peptide inhibits the B55α and Eya3 interaction in vitro. The B55i peptide expressed on a plasmid increases Myc pT58 and decreases Myc protein levels in TNBC cells, suggesting the potential of B55i or similar peptides as therapies for TNBC.
History
DepositionJan 24, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 18, 2025Provider: repository / Type: Initial release
Revision 1.0Jun 18, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 18, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jun 18, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 18, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 18, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 18, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jul 9, 2025Group: Data collection / Database references / Category: citation / em_admin / Item: _citation.journal_volume / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform
B: Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform
C: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
D: Protein phosphatase EYA3


Theoretical massNumber of molelcules
Total (without water)215,4144
Polymers215,4144
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 Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform / Medium tumor antigen-associated 61 kDa protein / PP2A subunit A isoform PR65-alpha / PP2A subunit A ...Medium tumor antigen-associated 61 kDa protein / PP2A subunit A isoform PR65-alpha / PP2A subunit A isoform R1-alpha


Mass: 64957.980 Da / Num. of mol.: 1 / Fragment: residues 9-589
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPP2R1A / Production host: Homo sapiens (human) / References: UniProt: P30153
#2: Protein Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform / PP2A subunit B isoform B55-alpha / PP2A subunit B isoform PR55-alpha / PP2A subunit B isoform R2- ...PP2A subunit B isoform B55-alpha / PP2A subunit B isoform PR55-alpha / PP2A subunit B isoform R2-alpha / PP2A subunit B isoform alpha


Mass: 52101.340 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPP2R2A / Production host: Homo sapiens (human) / References: UniProt: P63151
#3: Protein Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform / PP2A-alpha / Replication protein C / RP-C


Mass: 35636.152 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPP2CA / Production host: Homo sapiens (human)
References: UniProt: P67775, protein-serine/threonine phosphatase
#4: Protein Protein phosphatase EYA3 / Eyes absent homolog 3


Mass: 62718.516 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EYA3 / Production host: Escherichia coli (E. coli) / References: UniProt: Q99504, protein-tyrosine-phosphatase
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: PP2A-B55 and Eya3 complex / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightValue: 0.160 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
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: TFS KRIOS
Electron gunElectron source: OTHER / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: OTHER / Nominal defocus max: 2000 nm / Nominal defocus min: 600 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Image recordingElectron dose: 1.004 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21_5207 / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.71 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 159895 / Symmetry type: POINT
RefinementHighest resolution: 3.71 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)

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