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- EMDB-25363: The structure of the PP2A-B56gamma1 holoenzyme-PME-1 complex -

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Entry
Database: EMDB / ID: EMD-25363
TitleThe structure of the PP2A-B56gamma1 holoenzyme-PME-1 complex
Map data
Sample
  • Complex: The structure of PP2A-B56gamma holoenzyme-PME-1 complex
    • Protein or peptide: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform
    • Protein or peptide: Isoform Gamma-1 of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform
    • Protein or peptide: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
    • Protein or peptide: Protein phosphatase methylesterase 1
KeywordsThe structure of PP2A-B56gamma holoenzyme-PME-1 complex / RECOMBINATION
Function / homology
Function and homology information


protein phosphatase methylesterase-1 / : / 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 ...protein phosphatase methylesterase-1 / : / 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 / protein demethylation / : / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / female meiotic nuclear division / Inhibition of replication initiation of damaged DNA by RB1/E2F1 / meiotic sister chromatid cohesion / 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 / 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 / protein phosphatase inhibitor 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 / lncRNA binding / 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 / protein phosphatase activator activity / chromosome, centromeric region / DARPP-32 events / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of protein serine/threonine kinase activity / lateral plasma membrane / negative regulation of hippo signaling / 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 / DNA damage response, signal transduction by p53 class mediator / protein phosphatase 2A binding / 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 / spindle pole / Negative regulation of MAPK pathway
Similarity search - Function
Protein phosphatase methylesterase, eukaryotic / Protein phosphatase 2A, regulatory B subunit, B56 / Protein phosphatase 2A regulatory B subunit (B56 family) / : / : / HEAT repeat / HEAT repeat / Lipases, serine active site. / : / PPP2R1A-like HEAT repeat ...Protein phosphatase methylesterase, eukaryotic / Protein phosphatase 2A, regulatory B subunit, B56 / Protein phosphatase 2A regulatory B subunit (B56 family) / : / : / HEAT repeat / HEAT repeat / Lipases, serine active site. / : / PPP2R1A-like HEAT repeat / Serine/threonine specific protein phosphatases signature. / Protein phosphatase 2A homologues, catalytic domain. / Alpha/beta hydrolase family / 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 / Alpha/beta hydrolase fold-1 / Armadillo-like helical / Alpha/Beta hydrolase fold / 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 gamma isoform / Protein phosphatase methylesterase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsLi Y / Balakrishnan VK
Funding support3 items
OrganizationGrant numberCountry
American Cancer SocietyRSG-10-153-01-DMC
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM096060-01
Other privateA19-3376-5007
Citation
Journal: Elife / Year: 2022
Title: Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition.
Authors: Yitong Li / Vijaya Kumar Balakrishnan / Michael Rowse / Cheng-Guo Wu / Anastasia Phoebe Bravos / Vikash K Yadav / Ylva Ivarsson / Stefan Strack / Irina V Novikova / Yongna Xing /
Abstract: Protein phosphatase 2A (PP2A) holoenzymes target broad substrates by recognizing short motifs via regulatory subunits. PP2A methylesterase 1 (PME-1) is a cancer-promoting enzyme and undergoes ...Protein phosphatase 2A (PP2A) holoenzymes target broad substrates by recognizing short motifs via regulatory subunits. PP2A methylesterase 1 (PME-1) is a cancer-promoting enzyme and undergoes methylesterase activation upon binding to the PP2A core enzyme. Here, we showed that PME-1 readily demethylates different families of PP2A holoenzymes and blocks substrate recognition in vitro. The high-resolution cryoelectron microscopy structure of a PP2A-B56 holoenzyme-PME-1 complex reveals that PME-1 disordered regions, including a substrate-mimicking motif, tether to the B56 regulatory subunit at remote sites. They occupy the holoenzyme substrate-binding groove and allow large structural shifts in both holoenzyme and PME-1 to enable multipartite contacts at structured cores to activate the methylesterase. B56 interface mutations selectively block PME-1 activity toward PP2A-B56 holoenzymes and affect the methylation of a fraction of total cellular PP2A. The B56 interface mutations allow us to uncover B56-specific PME-1 functions in p53 signaling. Our studies reveal multiple mechanisms of PME-1 in suppressing holoenzyme functions and versatile PME-1 activities derived from coupling substrate-mimicking motifs to dynamic structured cores.
#1: Journal: Acta Crystallogr., Sect. D: Biol. Crystallogr. / Year: 2018
Title: Real-space refinement in PHENIX for cryo-EM and crystallography
Authors: Xing Y
History
DepositionNov 1, 2021-
Header (metadata) releaseAug 31, 2022-
Map releaseAug 31, 2022-
UpdateJun 5, 2024-
Current statusJun 5, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25363.png

Downloads & links

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Map

FileDownload / File: emd_25363.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.53 Å/pix.
x 480 pix.
= 254.4 Å		0.53 Å/pix.
x 480 pix.
= 254.4 Å		0.53 Å/pix.
x 480 pix.
= 254.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.53 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.07003537 - 0.18328618
Average (Standard dev.)0.00009027806 (±0.0075679645)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 254.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : The structure of PP2A-B56gamma holoenzyme-PME-1 complex

EntireName: The structure of PP2A-B56gamma holoenzyme-PME-1 complex
Components
  • Complex: The structure of PP2A-B56gamma holoenzyme-PME-1 complex
    • Protein or peptide: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform
    • Protein or peptide: Isoform Gamma-1 of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform
    • Protein or peptide: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
    • Protein or peptide: Protein phosphatase methylesterase 1

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Supramolecule #1: The structure of PP2A-B56gamma holoenzyme-PME-1 complex

SupramoleculeName: The structure of PP2A-B56gamma holoenzyme-PME-1 complex
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
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: Escherichia coli (E. coli)
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: Isoform Gamma-1 of Serine/threonine-protein phosphatase 2A 56 kDa...

MacromoleculeName: Isoform Gamma-1 of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 52.69527 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MLTCNKAGSR MVVDAANSNG PFQPVVLLHI RDVPPADQEK LFIQKLRQCC VLFDFVSDPL SDLKWKEVKR AALSEMVEYI THNRNVITE PIYPEVVHMF AVNMFRTLPP SSNPTGAEFD PEEDEPTLEA AWPHLQLVYE FFLRFLESPD FQPNIAKKYI D QKFVLQLL ...String:
MLTCNKAGSR MVVDAANSNG PFQPVVLLHI RDVPPADQEK LFIQKLRQCC VLFDFVSDPL SDLKWKEVKR AALSEMVEYI THNRNVITE PIYPEVVHMF AVNMFRTLPP SSNPTGAEFD PEEDEPTLEA AWPHLQLVYE FFLRFLESPD FQPNIAKKYI D QKFVLQLL ELFDSEDPRE RDFLKTTLHR IYGKFLGLRA YIRKQINNIF YRFIYETEHH NGIAELLEIL GSIINGFALP LK EEHKIFL LKVLLPLHKV KSLSVYHPQL AYCVVQFLEK DSTLTEPVVM ALLKYWPKTH SPKEVMFLNE LEEILDVIEP SEF VKIMEP LFRQLAKCVS SPHFQVAERA LYYWNNEYIM SLISDNAAKI LPIMFPSLYR NSKTHWNKTI HGLIYNALKL FMEM NQKLF DDCTQQFKAE KLKEKLKMKE REEAWVKIEN LAKANPQVLK KRIT

UniProtKB: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma 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: Protein phosphatase methylesterase 1

MacromoleculeName: Protein phosphatase methylesterase 1 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO / EC number: protein phosphatase methylesterase-1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.352379 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MSALEKSMHL GRLPSRPPLP GSGGSQSGAK MRMGPGRKRD FSPVPWSQYF ESMEDVEVEN ETGKDTFRVY KSGSEGPVLL LLHGGGHSA LSWAVFTAAI ISRVQCRIVA LDLRSHGETK VKNPEDLSAE TMAKDVGNVV EAMYGDLPPP IMLIGHAMGG A IAVHTASS ...String:
MSALEKSMHL GRLPSRPPLP GSGGSQSGAK MRMGPGRKRD FSPVPWSQYF ESMEDVEVEN ETGKDTFRVY KSGSEGPVLL LLHGGGHSA LSWAVFTAAI ISRVQCRIVA LDLRSHGETK VKNPEDLSAE TMAKDVGNVV EAMYGDLPPP IMLIGHAMGG A IAVHTASS NLVPSLLGLC MIDVVEGTAM DALNSMQNFL RGRPKTFKSL ENAIEWSVKS GQIRNLESAR VSMVGQVKQC EG ITSPEGS KSIVEGIIEE EEEDEEGSES ISKRKKEDDM ETKKDHPYTW RIELAKTEKY WDGWFRGLSN LFLSCPIPKL LLL AGVDRL DKDLTIGQMQ GKFQMQVLPQ CGHAVHEDAP DKVAEAVATF LIRHRFAEPI GGFQCVFPGC

UniProtKB: Protein phosphatase methylesterase 1

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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

Concentration1 mg/mL
BufferpH: 8
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 1.5 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: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 276737
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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