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- EMDB-42018: The structure of the PP2A-B56Delta holoenzyme mutant - E197K -

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Basic information

Entry
Database: EMDB / ID: EMD-42018
TitleThe structure of the PP2A-B56Delta holoenzyme mutant - E197K
Map data
Sample
  • Complex: Protein Phosphatase 2A B56 Delta holoenzyme mutant - E197K
    • Protein or peptide: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform
    • Protein or peptide: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform
    • Protein or peptide: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
  • Ligand: MANGANESE (II) ION
Keywordscomplex / phosphatase / CELL CYCLE
Function / homology
Function and homology information


meiotic spindle elongation / Integration of energy metabolism / PP2A-mediated dephosphorylation of key metabolic factors / regulation of microtubule binding / MASTL Facilitates Mitotic Progression / regulation of meiotic cell cycle process involved in oocyte maturation / mitotic sister chromatid separation / protein serine/threonine phosphatase complex / protein phosphatase type 2A complex / meiotic sister chromatid cohesion, centromeric ...meiotic spindle elongation / Integration of energy metabolism / PP2A-mediated dephosphorylation of key metabolic factors / regulation of microtubule binding / MASTL Facilitates Mitotic Progression / regulation of meiotic cell cycle process involved in oocyte maturation / mitotic sister chromatid separation / protein serine/threonine phosphatase complex / protein phosphatase type 2A complex / meiotic sister chromatid cohesion, centromeric / peptidyl-serine dephosphorylation / peptidyl-threonine dephosphorylation / FAR/SIN/STRIPAK complex / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / positive regulation of microtubule binding / Inhibition of replication initiation of damaged DNA by RB1/E2F1 / female meiotic nuclear division / protein antigen binding / GABA receptor binding / protein phosphatase regulator activity / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / Initiation of Nuclear Envelope (NE) Reformation / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / ERKs are inactivated / 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 / Disassembly of the destruction complex and recruitment of AXIN to the membrane / negative regulation of epithelial to mesenchymal transition / negative regulation of glycolytic process through fructose-6-phosphate / positive regulation of NLRP3 inflammasome complex assembly / Platelet sensitization by LDL / CTLA4 inhibitory signaling / protein serine/threonine phosphatase activity / myosin phosphatase activity / protein-serine/threonine phosphatase / regulation of cell differentiation / T cell homeostasis / negative regulation of peptidyl-threonine phosphorylation / ERK/MAPK targets / mesoderm development / protein phosphatase activator activity / regulation of G1/S transition of mitotic cell cycle / phosphoprotein phosphatase activity / chromosome, centromeric region / DARPP-32 events / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / lateral plasma membrane / negative regulation of hippo signaling / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / Cyclin A/B1/B2 associated events during G2/M transition / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / : / Recruitment of mitotic centrosome proteins and complexes / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / Resolution of Sister Chromatid Cohesion / protein dephosphorylation / AURKA Activation by TPX2 / protein tyrosine phosphatase activity / meiotic cell cycle / chromosome segregation / RHO GTPases Activate Formins / response to lead ion / RAF activation / Spry regulation of FGF signaling / regulation of protein phosphorylation / positive regulation of protein serine/threonine kinase activity / tau protein binding / Degradation of beta-catenin by the destruction complex / PKR-mediated signaling / spindle pole / Negative regulation of MAPK pathway / Separation of Sister Chromatids / Cyclin D associated events in G1 / microtubule cytoskeleton / Regulation of PLK1 Activity at G2/M Transition / Regulation of TP53 Degradation / mitotic cell cycle / nervous system development / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein-containing complex assembly / intracellular signal transduction / neuron projection / protein heterodimerization activity / membrane raft / neuronal cell body / glutamatergic synapse / dendrite / synapse
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. / Serine/threonine-specific protein phosphatase/bis(5-nucleosyl)-tetraphosphatase ...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 / Calcineurin-like phosphoesterase domain, ApaH type / Calcineurin-like phosphoesterase / Metallo-dependent phosphatase-like / Armadillo-like helical / Armadillo-type fold
Similarity search - Domain/homology
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 delta isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsWu CG / Xing Y
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM137090-01 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2024
Title: B56δ long-disordered arms form a dynamic PP2A regulation interface coupled with global allostery and Jordan's syndrome mutations.
Authors: Cheng-Guo Wu / Vijaya K Balakrishnan / Ronald A Merrill / Pankaj S Parihar / Kirill Konovolov / Yu-Chia Chen / Zhen Xu / Hui Wei / Ramya Sundaresan / Qiang Cui / Brian E Wadzinski / Mark R ...Authors: Cheng-Guo Wu / Vijaya K Balakrishnan / Ronald A Merrill / Pankaj S Parihar / Kirill Konovolov / Yu-Chia Chen / Zhen Xu / Hui Wei / Ramya Sundaresan / Qiang Cui / Brian E Wadzinski / Mark R Swingle / Alla Musiyenko / Wendy K Chung / Richard E Honkanen / Aussie Suzuki / Xuhui Huang / Stefan Strack / Yongna Xing /
Abstract: Intrinsically disordered regions (IDR) and short linear motifs (SLiMs) play pivotal roles in the intricate signaling networks governed by phosphatases and kinases. B56δ (encoded by ) is a regulatory ...Intrinsically disordered regions (IDR) and short linear motifs (SLiMs) play pivotal roles in the intricate signaling networks governed by phosphatases and kinases. B56δ (encoded by ) is a regulatory subunit of protein phosphatase 2A (PP2A) with long IDRs that harbor a substrate-mimicking SLiM and multiple phosphorylation sites. De novo missense mutations in cause intellectual disabilities (ID), macrocephaly, Parkinsonism, and a broad range of neurological symptoms. Our single-particle cryo-EM structures of the PP2A-B56δ holoenzyme reveal that the long, disordered arms at the B56δ termini fold against each other and the holoenzyme core. This architecture suppresses both the phosphatase active site and the substrate-binding protein groove, thereby stabilizing the enzyme in a closed latent form with dual autoinhibition. The resulting interface spans over 190 Å and harbors unfavorable contacts, activation phosphorylation sites, and nearly all residues with ID-associated mutations. Our studies suggest that this dynamic interface is coupled to an allosteric network responsive to phosphorylation and altered globally by mutations. Furthermore, we found that ID mutations increase the holoenzyme activity and perturb the phosphorylation rates, and the severe variants significantly increase the mitotic duration and error rates compared to the normal variant.
History
DepositionSep 16, 2023-
Header (metadata) releaseJan 10, 2024-
Map releaseJan 10, 2024-
UpdateJan 10, 2024-
Current statusJan 10, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42018.png

Downloads & links

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Map

FileDownload / File: emd_42018.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 256 pix.
= 273.408 Å		1.07 Å/pix.
x 256 pix.
= 273.408 Å		1.07 Å/pix.
x 256 pix.
= 273.408 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.068 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.33
Minimum - Maximum-0.75342786 - 1.2787349
Average (Standard dev.)0.0002909812 (±0.037486028)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 273.408 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_42018_half_map_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_42018_half_map_2.map
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Histogram (log scale)

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Sample components

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Entire : Protein Phosphatase 2A B56 Delta holoenzyme mutant - E197K

EntireName: Protein Phosphatase 2A B56 Delta holoenzyme mutant - E197K
Components
  • Complex: Protein Phosphatase 2A B56 Delta holoenzyme mutant - E197K
    • Protein or peptide: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform
    • Protein or peptide: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform
    • Protein or peptide: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
  • Ligand: MANGANESE (II) ION

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Supramolecule #1: Protein Phosphatase 2A B56 Delta holoenzyme mutant - E197K

SupramoleculeName: Protein Phosphatase 2A B56 Delta holoenzyme mutant - E197K
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit...

MacromoleculeName: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 65.378344 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MAAADGDDSL YPIAVLIDEL RNEDVQLRLN SIKKLSTIAL ALGVERTRSE LLPFLTDTIY DEDEVLLALA EQLGTFTTLV GGPEYVHCL LPPLESLATV EETVVRDKAV ESLRAISHEH SPSDLEAHFV PLVKRLAGGD WFTSRTSACG LFSVCYPRVS S AVKAELRQ ...String:
MAAADGDDSL YPIAVLIDEL RNEDVQLRLN SIKKLSTIAL ALGVERTRSE LLPFLTDTIY DEDEVLLALA EQLGTFTTLV GGPEYVHCL LPPLESLATV EETVVRDKAV ESLRAISHEH SPSDLEAHFV PLVKRLAGGD WFTSRTSACG LFSVCYPRVS S AVKAELRQ YFRNLCSDDT PMVRRAAASK LGEFAKVLEL DNVKSEIIPM FSNLASDEQD SVRLLAVEAC VNIAQLLPQE DL EALVMPT LRQAAEDKSW RVRYMVADKF TELQKAVGPE ITKTDLVPAF QNLMKDCEAE VRAAASHKVK EFCENLSADC REN VIMSQI LPCIKELVSD ANQHVKSALA SVIMGLSPIL GKDNTIEHLL PLFLAQLKDE CPEVRLNIIS NLDCVNEVIG IRQL SQSLL PAIVELAEDA KWRVRLAIIE YMPLLAGQLG VEFFDEKLNS LCMAWLVDHV YAIREAATSN LKKLVEKFGK EWAHA TIIP KVLAMSGDPN YLHRMTTLFC INVLSEVCGQ DITTKHMLPT VLRMAGDPVA NVRFNVAKSL QKIGPILDNS TLQSEV KPI LEKLTQDQDV DVKYFAQEAL TVLSLA

UniProtKB: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform

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Macromolecule #2: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit...

MacromoleculeName: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 70.089742 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MPYKLKKEKE PPKVAKCTAK PSSSGKDGGG ENTEEAQPQP QPQPQPQAQS QPPSSNKRPS NSTPPPTQLS KIKYSGGPQI VKKERRQSS SRFNLSKNRE LQKLPALKDS PTQEREELFI QKLRQCCVLF DFVSDPLSDL KFKEVKRAGL NEMVEYITHS R DVVTEAIY ...String:
MPYKLKKEKE PPKVAKCTAK PSSSGKDGGG ENTEEAQPQP QPQPQPQAQS QPPSSNKRPS NSTPPPTQLS KIKYSGGPQI VKKERRQSS SRFNLSKNRE LQKLPALKDS PTQEREELFI QKLRQCCVLF DFVSDPLSDL KFKEVKRAGL NEMVEYITHS R DVVTEAIY PEAVTMFSVN LFRTLPPSSN PTGAEFDPKE DEPTLEAAWP HLQLVYEFFL RFLESPDFQP NIAKKYIDQK FV LALLDLF DSEDPRERDF LKTILHRIYG KFLGLRAYIR RQINHIFYRF IYETEHHNGI AELLEILGSI INGFALPLKE EHK MFLIRV LLPLHKVKSL SVYHPQLAYC VVQFLEKESS LTEPVIVGLL KFWPKTHSPK EVMFLNELEE ILDVIEPSEF SKVM EPLFR QLAKCVSSPH FQVAERALYY WNNEYIMSLI SDNAARVLPI MFPALYRNSK SHWNKTIHGL IYNALKLFME MNQKL FDDC TQQYKAEKQK GRFRMKEREE MWQKIEELAR LNPQYPMFRA PPPLPPVYSM ETETPTAEDI QLLKRTVETE AVQMLK DIK KEKVLLRRKS ELPQDVYTIK ALEAHKRAEE FLTASQEAL

UniProtKB: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform

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Macromolecule #3: Serine/threonine-protein phosphatase 2A catalytic subunit alpha i...

MacromoleculeName: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
type: protein_or_peptide / ID: 3 / Number of copies: 1 / 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 #4: MANGANESE (II) ION

MacromoleculeName: MANGANESE (II) ION / type: ligand / ID: 4 / Number of copies: 2 / 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

Concentration0.4 mg/mL
BufferpH: 8
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 49.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.7000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: Ab initio model generated by cryoSparc
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 276448
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD

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