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- PDB-6nts: Protein Phosphatase 2A (Aalpha-B56alpha-Calpha) holoenzyme in com... -

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Entry
Database: PDB / ID: 6nts
TitleProtein Phosphatase 2A (Aalpha-B56alpha-Calpha) holoenzyme in complex with a Small Molecule Activator of PP2A (SMAP)
Components
  • Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform
  • Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform
  • Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
KeywordsHYDROLASE/ACTIVATOR / Holoenzyme complex / Phosphatase / Activator / HYDROLASE-ACTIVATOR complex
Function / homology
Function and homology information


meiotic spindle elongation / Integration of energy metabolism / PP2A-mediated dephosphorylation of key metabolic factors / MASTL Facilitates Mitotic Progression / regulation of meiotic cell cycle process involved in oocyte maturation / mitotic sister chromatid separation / protein phosphatase type 2A complex / protein serine/threonine phosphatase complex / peptidyl-threonine dephosphorylation / meiotic sister chromatid cohesion, centromeric ...meiotic spindle elongation / Integration of energy metabolism / PP2A-mediated dephosphorylation of key metabolic factors / MASTL Facilitates Mitotic Progression / regulation of meiotic cell cycle process involved in oocyte maturation / mitotic sister chromatid separation / protein phosphatase type 2A complex / protein serine/threonine phosphatase complex / peptidyl-threonine dephosphorylation / meiotic sister chromatid cohesion, centromeric / peptidyl-serine dephosphorylation / FAR/SIN/STRIPAK complex / : / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / female meiotic nuclear division / Inhibition of replication initiation of damaged DNA by RB1/E2F1 / GABA receptor binding / protein phosphatase regulator activity / protein antigen binding / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / 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 / M band / Disassembly of the destruction complex and recruitment of AXIN to the membrane / negative regulation of epithelial to mesenchymal transition / Co-inhibition by CTLA4 / protein serine/threonine phosphatase activity / Platelet sensitization by LDL / histone H2AXS140 phosphatase activity / RNA polymerase II CTD heptapeptide repeat Y1 phosphatase activity / RNA polymerase II CTD heptapeptide repeat T4 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity / MAP kinase serine/threonine phosphatase activity / calmodulin-dependent protein phosphatase activity / myosin phosphatase activity / protein-serine/threonine phosphatase / negative regulation of glycolytic process through fructose-6-phosphate / positive regulation of NLRP3 inflammasome complex assembly / ERK/MAPK targets / T cell homeostasis / mesoderm development / vascular endothelial cell response to oscillatory fluid shear stress / regulation of cell differentiation / regulation of G1/S transition of mitotic cell cycle / phosphoprotein phosphatase activity / chromosome, centromeric region / DARPP-32 events / positive regulation of protein serine/threonine kinase activity / lateral plasma membrane / negative regulation of hippo signaling / negative regulation of protein localization to plasma membrane / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / Cyclin A/B1/B2 associated events during G2/M transition / spindle assembly / protein dephosphorylation / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / protein tyrosine phosphatase activity / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / Resolution of Sister Chromatid Cohesion / AURKA Activation by TPX2 / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / meiotic cell cycle / chromosome segregation / RHO GTPases Activate Formins / RAF activation / response to lead ion / Spry regulation of FGF signaling / PKR-mediated signaling / Degradation of beta-catenin by the destruction complex / tau protein binding / Z disc / kinase binding / spindle pole / Negative regulation of MAPK pathway / Cyclin D associated events in G1 / Separation of Sister Chromatids / Regulation of TP53 Degradation / Regulation of PLK1 Activity at G2/M Transition / mitotic cell cycle / microtubule cytoskeleton
Similarity search - Function
Protein phosphatase 2A, regulatory B subunit, B56 / Protein phosphatase 2A regulatory B subunit (B56 family) / : / : / HEAT repeat / HEAT repeat / : / PPP2R1A-like HEAT repeat / Serine/threonine specific protein phosphatases signature. / Protein phosphatase 2A homologues, catalytic domain. ...Protein phosphatase 2A, regulatory B subunit, B56 / Protein phosphatase 2A regulatory B subunit (B56 family) / : / : / 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 repeat profile. / HEAT, type 2 / HEAT repeats / Metallo-dependent phosphatases / Purple Acid Phosphatase; chain A, domain 2 / Calcineurin-like phosphoesterase domain, ApaH type / Calcineurin-like phosphoesterase / Leucine-rich Repeat Variant / Metallo-dependent phosphatase-like / Leucine-rich Repeat Variant / 4-Layer Sandwich / Armadillo-like helical / Alpha Horseshoe / Armadillo-type fold / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-L2J / : / Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform / Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform / Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.63 Å
AuthorsHuang, W. / Taylor, D.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)DP2CA186571 United States
CitationJournal: Cell / Year: 2020
Title: Selective PP2A Enhancement through Biased Heterotrimer Stabilization.
Authors: Daniel Leonard / Wei Huang / Sudeh Izadmehr / Caitlin M O'Connor / Danica D Wiredja / Zhizhi Wang / Nilesh Zaware / Yinghua Chen / Daniela M Schlatzer / Janna Kiselar / Nikhil Vasireddi / ...Authors: Daniel Leonard / Wei Huang / Sudeh Izadmehr / Caitlin M O'Connor / Danica D Wiredja / Zhizhi Wang / Nilesh Zaware / Yinghua Chen / Daniela M Schlatzer / Janna Kiselar / Nikhil Vasireddi / Stefan Schüchner / Abbey L Perl / Matthew D Galsky / Wenqing Xu / David L Brautigan / Egon Ogris / Derek J Taylor / Goutham Narla /
Abstract: Impairment of protein phosphatases, including the family of serine/threonine phosphatases designated PP2A, is essential for the pathogenesis of many diseases, including cancer. The ability of PP2A to ...Impairment of protein phosphatases, including the family of serine/threonine phosphatases designated PP2A, is essential for the pathogenesis of many diseases, including cancer. The ability of PP2A to dephosphorylate hundreds of proteins is regulated by over 40 specificity-determining regulatory "B" subunits that compete for assembly and activation of heterogeneous PP2A heterotrimers. Here, we reveal how a small molecule, DT-061, specifically stabilizes the B56α-PP2A holoenzyme in a fully assembled, active state to dephosphorylate selective substrates, such as its well-known oncogenic target, c-Myc. Our 3.6 Å structure identifies molecular interactions between DT-061 and all three PP2A subunits that prevent dissociation of the active enzyme and highlight inherent mechanisms of PP2A complex assembly. Thus, our findings provide fundamental insights into PP2A complex assembly and regulation, identify a unique interfacial stabilizing mode of action for therapeutic targeting, and aid in the development of phosphatase-based therapeutics tailored against disease specific phospho-protein targets.
History
DepositionJan 30, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 6, 2020Provider: repository / Type: Initial release
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Revision 1.1May 13, 2020Group: Database references / Category: citation
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Revision 2.0Nov 15, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / database_2 / struct_conn / struct_conn_type
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn_type.id
Revision 2.1Nov 6, 2024Group: Data collection / Structure summary
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Structure visualization

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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 56 kDa regulatory subunit alpha isoform
C: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)157,2976
Polymers156,6663
Non-polymers6303
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area6080 Å2
ΔGint-27 kcal/mol
Surface area55380 Å2

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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: 65378.344 Da / Num. of mol.: 1
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 56 kDa regulatory subunit alpha isoform / PP2A B subunit isoform B'-alpha / PP2A B subunit isoform B56-alpha / PP2A B subunit isoform PR61- ...PP2A B subunit isoform B'-alpha / PP2A B subunit isoform B56-alpha / PP2A B subunit isoform PR61-alpha / PR61alpha / PP2A B subunit isoform R5-alpha


Mass: 56266.555 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPP2R5A / Production host: Escherichia coli (E. coli) / References: UniProt: Q15172
#3: Protein Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform / PP2A-alpha / Replication protein C / RP-C


Mass: 35021.500 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPP2CA / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P67775, protein-serine/threonine phosphatase
#4: Chemical ChemComp-L2J / N-[(1R,2R,3S)-2-hydroxy-3-(10H-phenoxazin-10-yl)cyclohexyl]-4-(trifluoromethoxy)benzene-1-sulfonamide


Mass: 520.521 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C25H23F3N2O5S / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: Mn
Has ligand of interestY
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 Aalpha-B56alpha-Calpha holoenzyme in complex with a Small Molecule Activator of PP2A (SMAP)
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.02
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
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: SPOT SCAN
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18rc3_3805: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.63 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 83784 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 139.2 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00210161
ELECTRON MICROSCOPYf_angle_d0.44713781
ELECTRON MICROSCOPYf_dihedral_angle_d14.2561339
ELECTRON MICROSCOPYf_chiral_restr0.0341572
ELECTRON MICROSCOPYf_plane_restr0.0021765

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