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- PDB-9c7t: PP2A:B55-Eya3 substrate complex -

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Basic information

Entry
Database: PDB / ID: 9c7t
TitlePP2A:B55-Eya3 substrate complex
Components
  • (Serine/threonine-protein phosphatase 2A ...) x 3
  • Eyes absent homolog 3
KeywordsHYDROLASE/SUBSTRATE / PP2A:B55 / Eya3 / substrate complex / HYDROLASE / HYDROLASE-SUBSTRATE complex
Function / homology
Function and homology information


histone H2AXY142 phosphatase activity / regulation of chromosome segregation / 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 / meiotic sister chromatid cohesion, centromeric / protein serine/threonine phosphatase complex ...histone H2AXY142 phosphatase activity / regulation of chromosome segregation / 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 / meiotic sister chromatid cohesion, centromeric / protein serine/threonine phosphatase 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 / regulation of transcription elongation by RNA polymerase II / 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 / T cell homeostasis / 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 / Initiation of Nuclear Envelope (NE) Reformation / Co-stimulation by CD28 / RNA polymerase II transcription initiation surveillance / integrator complex / 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 / response to ionizing radiation / ERK/MAPK targets / vascular endothelial cell response to oscillatory fluid shear stress / regulation of cell differentiation / protein serine/threonine phosphatase activity / regulation of microtubule polymerization / positive regulation of NLRP3 inflammasome complex assembly / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / DARPP-32 events / lateral plasma membrane / chromosome, centromeric region / anatomical structure morphogenesis / enzyme-substrate adaptor activity / negative regulation of hippo signaling / visual perception / Cyclin A/B1/B2 associated events during G2/M transition / spindle assembly / regulation of G1/S transition of mitotic cell cycle / phosphoprotein phosphatase activity / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / 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 / Recruitment of NuMA to mitotic centrosomes / protein tyrosine phosphatase activity / Anchoring of the basal body to the plasma membrane / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / protein phosphatase 2A binding / AURKA Activation by TPX2 / positive regulation of DNA repair / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Resolution of Sister Chromatid Cohesion / chromosome segregation / negative regulation of canonical Wnt signaling pathway / RHO GTPases Activate Formins / RAF activation / Spry regulation of FGF signaling / PKR-mediated signaling / response to lead ion / tau protein binding / Degradation of beta-catenin by the destruction complex / double-strand break repair / microtubule cytoskeleton / Cyclin D associated events in G1 / Negative regulation of MAPK pathway / Separation of Sister Chromatids / Regulation of TP53 Degradation / mitotic cell cycle / Regulation of PLK1 Activity at G2/M Transition / cell differentiation / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / spindle pole
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: 2.7 Å
AuthorsPage, R. / Peti, W. / Padi, S. / Godek, R.J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM144379 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM144483 United States
Citation
Journal: Nat Struct Mol Biol / Year: 2025
Title: Cryo-EM structures of PP2A:B55 with p107 and Eya3 define substrate recruitment.
Authors: Sathish K R Padi / Rachel J Godek / Wolfgang Peti / Rebecca Page /
Abstract: Phosphoprotein phosphatases (PPPs) achieve specificity by binding substrates and regulators using PPP-specific short motifs. Protein phosphatase 2A (PP2A) is a highly conserved phosphatase that ...Phosphoprotein phosphatases (PPPs) achieve specificity by binding substrates and regulators using PPP-specific short motifs. Protein phosphatase 2A (PP2A) is a highly conserved phosphatase that regulates cell signaling and is a tumor suppressor. Here, we use cryo-electron microscopy and nuclear magnetic resonance (NMR) spectroscopy to investigate the mechanisms of human p107 substrate and Eya3 regulator recruitment to the PP2A:B55 holoenzyme. We show that, while they associate with B55 using a common set of interaction pockets, the mechanism of substrate and regulator binding differs and is distinct from that observed for PP2A:B56 and other PPPs. We also identify the core B55 recruitment motif in Eya3 proteins, a sequence conserved amongst the Eya family. Lastly, using NMR-based dephosphorylation assays, we demonstrate how B55 recruitment directs PP2A:B55 fidelity through the selective dephosphorylation of specific phosphosites. As PP2A:B55 orchestrates mitosis and DNA damage repair, these data provide a roadmap for pursuing new avenues to therapeutically target this complex by individually blocking a subset of regulators that use different B55 interaction sites.
#1: Journal: Nature / Year: 2024
Title: Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19.
Authors: Sathish K R Padi / Margaret R Vos / Rachel J Godek / James R Fuller / Thomas Kruse / Jamin B Hein / Jakob Nilsson / Matthew S Kelker / Rebecca Page / Wolfgang Peti /
Abstract: Progression through the cell cycle is controlled by regulated and abrupt changes in phosphorylation. Mitotic entry is initiated by increased phosphorylation of mitotic proteins, a process driven by ...Progression through the cell cycle is controlled by regulated and abrupt changes in phosphorylation. Mitotic entry is initiated by increased phosphorylation of mitotic proteins, a process driven by kinases, whereas mitotic exit is achieved by counteracting dephosphorylation, a process driven by phosphatases, especially PP2A:B55. Although the role of kinases in mitotic entry is well established, recent data have shown that mitosis is only successfully initiated when the counterbalancing phosphatases are also inhibited. Inhibition of PP2A:B55 is achieved by the intrinsically disordered proteins ARPP19 and FAM122A. Despite their critical roles in mitosis, the mechanisms by which they achieve PP2A:B55 inhibition is unknown. Here, we report the single-particle cryo-electron microscopy structures of PP2A:B55 bound to phosphorylated ARPP19 and FAM122A. Consistent with our complementary NMR spectroscopy studies, both intrinsically disordered proteins bind PP2A:B55, but do so in highly distinct manners, leveraging multiple distinct binding sites on B55. Our extensive structural, biophysical and biochemical data explain how substrates and inhibitors are recruited to PP2A:B55 and provide a molecular roadmap for the development of therapeutic interventions for PP2A:B55-related diseases.
History
DepositionJun 11, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 21, 2025Provider: repository / Type: Initial release
Revision 1.1Aug 20, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _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: Eyes absent homolog 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)158,9766
Polymers158,8554
Non-polymers1212
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Serine/threonine-protein phosphatase 2A ... , 3 types, 3 molecules ABC

#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: Escherichia coli (E. coli) / 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: 35845.375 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

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Protein , 1 types, 1 molecules D

#4: Protein Eyes absent homolog 3


Mass: 5950.449 Da / Num. of mol.: 1 / Fragment: residues 62-108
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

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Non-polymers , 2 types, 2 molecules

#5: Chemical ChemComp-FE2 / FE (II) ION


Mass: 55.845 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Fe
#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn

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Details

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: PP2A:B55-EYA3 / Type: COMPLEX / Details: PP2A:B55 (PP2Aa-B55-PP2Ac) bound to EYA3 62-110 / Entity ID: #1-#4 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.158652 MDa / Experimental value: NO
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 600 nm
Image recordingAverage exposure time: 7 sec. / Electron dose: 51.04 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4607
EM imaging opticsEnergyfilter slit width: 10 eV
Image scansWidth: 4096 / Height: 4096

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2Topazparticle selection
3Leginonimage acquisition
5cryoSPARCCTF correction
8UCSF ChimeraXmodel fitting
9Cootmodel fitting
11cryoSPARCinitial Euler assignment
12cryoSPARCfinal Euler assignment
13cryoSPARCclassification
14cryoSPARC3D reconstruction
15PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 107919 / Details: GSFSC resolution (tight & corrected) / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00410873
ELECTRON MICROSCOPYf_angle_d0.51414738
ELECTRON MICROSCOPYf_dihedral_angle_d4.0251448
ELECTRON MICROSCOPYf_chiral_restr0.0421664
ELECTRON MICROSCOPYf_plane_restr0.0041906

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