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Open data
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Basic information
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Title | The structure of the PP2A-B56Delta holoenzyme mutant - E197K | |||||||||
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![]() | complex / phosphatase / CELL CYCLE | |||||||||
Function / homology | ![]() meiotic spindle elongation / Integration of energy metabolism / PP2A-mediated dephosphorylation of key metabolic factors / regulation of microtubule binding / protein serine/threonine phosphatase complex / mitotic sister chromatid separation / MASTL Facilitates Mitotic Progression / regulation of meiotic cell cycle process involved in oocyte maturation / 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 / protein serine/threonine phosphatase complex / mitotic sister chromatid separation / MASTL Facilitates Mitotic Progression / regulation of meiotic cell cycle process involved in oocyte maturation / protein phosphatase type 2A complex / meiotic sister chromatid cohesion, centromeric / peptidyl-serine dephosphorylation / peptidyl-threonine dephosphorylation / FAR/SIN/STRIPAK complex / positive regulation of microtubule binding / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / Inhibition of replication initiation of damaged DNA by RB1/E2F1 / female meiotic nuclear division / 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 / Initiation of Nuclear Envelope (NE) Reformation / ERKs are inactivated / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / 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 / negative regulation of epithelial to mesenchymal transition / regulation of growth / Disassembly of the destruction complex and recruitment of AXIN to the membrane / negative regulation of glycolytic process through fructose-6-phosphate / positive regulation of NLRP3 inflammasome complex assembly / myosin phosphatase activity / CTLA4 inhibitory signaling / protein serine/threonine phosphatase activity / Platelet sensitization by LDL / protein-serine/threonine phosphatase / regulation of cell differentiation / negative regulation of peptidyl-threonine phosphorylation / negative regulation of hippo signaling / ERK/MAPK targets / protein phosphatase activator activity / T cell homeostasis / regulation of G1/S transition of mitotic cell cycle / mesoderm development / phosphoprotein phosphatase activity / chromosome, centromeric region / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / DARPP-32 events / lateral plasma membrane / 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 / meiotic cell cycle / protein tyrosine phosphatase activity / chromosome segregation / RHO GTPases Activate Formins / response to lead ion / RAF activation / regulation of protein phosphorylation / Spry regulation of FGF signaling / Degradation of beta-catenin by the destruction complex / tau protein binding / positive regulation of protein serine/threonine kinase activity / 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 / synapse / dendrite Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.7 Å | |||||||||
![]() | Wu CG / Xing Y | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 33.2 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 19.5 KB 19.5 KB | Display Display | ![]() |
Images | ![]() | 64.9 KB | ||
Filedesc metadata | ![]() | 7 KB | ||
Others | ![]() ![]() | 59.3 MB 59.3 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8u1xMC ![]() 8u89C M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 1.068 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_41837_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_41837_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Protein Phosphatase 2A B56 Delta holoenzyme mutant - E197K
Entire | Name: Protein Phosphatase 2A B56 Delta holoenzyme mutant - E197K |
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Components |
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-Supramolecule #1: Protein Phosphatase 2A B56 Delta holoenzyme mutant - E197K
Supramolecule | Name: Protein Phosphatase 2A B56 Delta holoenzyme mutant - E197K type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit...
Macromolecule | Name: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 65.378344 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: 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 |
-Macromolecule #2: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit...
Macromolecule | Name: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 70.089742 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: 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 |
-Macromolecule #3: Serine/threonine-protein phosphatase 2A catalytic subunit alpha i...
Macromolecule | Name: 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 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 35.636152 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: 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 |
-Macromolecule #4: MANGANESE (II) ION
Macromolecule | Name: MANGANESE (II) ION / type: ligand / ID: 4 / Number of copies: 2 / Formula: MN |
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Molecular weight | Theoretical: 54.938 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 0.4 mg/mL |
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Buffer | pH: 8 |
Grid | Model: UltrAuFoil R1.2/1.3 / Material: GOLD / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 49.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination 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 model | Type of model: OTHER / Details: Ab initio model generated by cryoSparc |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 367763 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.0) |