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- PDB-7cun: The structure of human Integrator-PP2A complex -

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Basic information

Entry
Database: PDB / ID: 7cun
TitleThe structure of human Integrator-PP2A complex
Components
  • (Integrator complex subunit ...) x 9
  • PP2A-A
  • PP2A-C
  • unknown
KeywordsTRANSCRIPTION / Integrator-PP2A complex / phosphatase
Function / homology
Function and homology information


U2 snRNA 3'-end processing / snRNA processing / integrator complex / intercellular transport / snRNA 3'-end processing / meiotic spindle elongation / Integration of energy metabolism / PP2A-mediated dephosphorylation of key metabolic factors / regulation of microtubule binding / MASTL Facilitates Mitotic Progression ...U2 snRNA 3'-end processing / snRNA processing / integrator complex / intercellular transport / snRNA 3'-end processing / meiotic spindle elongation / Integration of energy metabolism / PP2A-mediated dephosphorylation of key metabolic factors / regulation of microtubule binding / MASTL Facilitates Mitotic Progression / mitotic sister chromatid separation / regulation of meiotic cell cycle process involved in oocyte maturation / protein phosphatase type 2A complex / meiotic sister chromatid cohesion, centromeric / peptidyl-serine dephosphorylation / : / regulation of transcription elongation by RNA polymerase II / peptidyl-threonine dephosphorylation / negative regulation of tyrosine phosphorylation of STAT protein / 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 antigen binding / ceramide metabolic process / protein phosphatase regulator activity / GABA receptor binding / negative regulation of epithelial to mesenchymal transition / 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 / Hydrolases; Acting on ester bonds; Endoribonucleases producing 3'-phosphomonoesters / 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 Wnt signaling pathway / regulation of growth / Disassembly of the destruction complex and recruitment of AXIN to the membrane / inner cell mass cell proliferation / negative regulation of glycolytic process through fructose-6-phosphate / positive regulation of NLRP3 inflammasome complex assembly / myosin phosphatase activity / protein serine/threonine phosphatase activity / CTLA4 inhibitory signaling / Platelet sensitization by LDL / negative regulation of MAPK cascade / protein-serine/threonine phosphatase / regulation of cell differentiation / T cell homeostasis / ERK/MAPK targets / regulation of G1/S transition of mitotic cell cycle / phosphoprotein phosphatase activity / regulation of DNA replication / mesoderm development / RNA polymerase II transcribes snRNA genes / chromosome, centromeric region / DARPP-32 events / lateral plasma membrane / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / regulation of cell adhesion / Cyclin A/B1/B2 associated events during G2/M transition / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / RNA endonuclease activity / embryo implantation / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / Resolution of Sister Chromatid Cohesion / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / AURKA Activation by TPX2 / protein dephosphorylation / RNA splicing / meiotic cell cycle / DNA damage checkpoint signaling / response to organic substance / protein tyrosine phosphatase activity / chromosome segregation / cellular response to ionizing radiation / RHO GTPases Activate Formins / response to lead ion / regulation of protein phosphorylation / negative regulation of transforming growth factor beta receptor signaling pathway / Spry regulation of FGF signaling / RAF activation / Degradation of beta-catenin by the destruction complex / PKR-mediated signaling / tau protein binding / positive regulation of protein serine/threonine kinase activity / negative regulation of cell growth / spindle pole
Similarity search - Function
Domain of unknown function DUF3677 / Integrator complex subunit 2, metazoa / Integrator complex subunit 2 / Integrator complex subunit 5, C-terminal / Integrator complex subunit 5, N-terminal / Integrator complex subunit 7 / Integrator complex subunit 8 / Integrator complex subunit 1 / Integrator complex subunit 5 / Protein of unknown function (DUF3677) ...Domain of unknown function DUF3677 / Integrator complex subunit 2, metazoa / Integrator complex subunit 2 / Integrator complex subunit 5, C-terminal / Integrator complex subunit 5, N-terminal / Integrator complex subunit 7 / Integrator complex subunit 8 / Integrator complex subunit 1 / Integrator complex subunit 5 / Protein of unknown function (DUF3677) / Integrator complex subunit 2 / Integrator complex subunit 5 N-terminus / Integrator complex subunit 5 C-terminus / INTS6/SAGE1/DDX26B/CT45, C-terminal / INTS6/SAGE1/DDX26B/CT45 C-terminus / HEAT repeat associated with sister chromatid cohesion / : / : / Integrator IntS9, C-terminal domain / Integrator IntS11, C-terminal domain / Integrator complex subunit 9 / Integrator complex subunit 11, MBL-fold / Sister chromatid cohesion protein PDS5 protein / Metallo-beta-lactamase superfamily domain / : / Beta-Casp domain / Beta-Casp domain / Beta-Casp domain / Zn-dependent metallo-hydrolase, RNA specificity domain / Zn-dependent metallo-hydrolase RNA specificity domain / HEAT repeat / 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 / von Willebrand factor type A domain / HEAT repeats / Calcineurin-like phosphoesterase domain, ApaH type / Calcineurin-like phosphoesterase / Metallo-dependent phosphatase-like / VWFA domain profile. / Metallo-beta-lactamase superfamily / Metallo-beta-lactamase / von Willebrand factor, type A / von Willebrand factor A-like domain superfamily / Ribonuclease Z/Hydroxyacylglutathione hydrolase-like / Armadillo-like helical / Tetratricopeptide-like helical domain superfamily / 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 / Integrator complex subunit 11 / Integrator complex subunit 5 / Integrator complex subunit 8 / Integrator complex subunit 1 / Integrator complex subunit 4 / Integrator complex subunit 2 / Integrator complex subunit 9 ...: / Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform / Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform / Integrator complex subunit 11 / Integrator complex subunit 5 / Integrator complex subunit 8 / Integrator complex subunit 1 / Integrator complex subunit 4 / Integrator complex subunit 2 / Integrator complex subunit 9 / Integrator complex subunit 7 / Integrator complex subunit 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsZheng, H. / Qi, Y. / Liu, W. / Li, J. / Wang, J. / Xu, Y.
CitationJournal: Science / Year: 2020
Title: Identification of Integrator-PP2A complex (INTAC), an RNA polymerase II phosphatase.
Authors: Hai Zheng / Yilun Qi / Shibin Hu / Xuan Cao / Congling Xu / Zhinang Yin / Xizi Chen / Yan Li / Weida Liu / Jie Li / Jiawei Wang / Gang Wei / Kaiwei Liang / Fei Xavier Chen / Yanhui Xu /
Abstract: The 14-subunit metazoan-specific Integrator contains an endonuclease that cleaves nascent RNA transcripts. Here, we identified a complex containing Integrator and protein phosphatase 2A core enzyme ...The 14-subunit metazoan-specific Integrator contains an endonuclease that cleaves nascent RNA transcripts. Here, we identified a complex containing Integrator and protein phosphatase 2A core enzyme (PP2A-AC), termed INTAC. The 3.5-angstrom-resolution structure reveals that nine human Integrator subunits and PP2A-AC assemble into a cruciform-shaped central scaffold formed by the backbone and shoulder modules, with the phosphatase and endonuclease modules flanking the opposite sides. As a noncanonical PP2A holoenzyme, the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7 and thus regulates transcription. Our study extends the function of PP2A to transcriptional regulation and reveals how dual enzymatic activities-RNA cleavage and RNA polymerase II dephosphorylation-are structurally and functionally integrated into the INTAC complex.
History
DepositionAug 23, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 25, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 9, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.pdbx_database_id_PubMed ..._citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation_author.identifier_ORCID / _citation_author.name

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Structure visualization

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Assembly

Deposited unit
A: Integrator complex subunit 1
B: Integrator complex subunit 2
D: Integrator complex subunit 4
E: Integrator complex subunit 5
F: Integrator complex subunit 6
G: Integrator complex subunit 7
H: Integrator complex subunit 8
I: Integrator complex subunit 9
K: Integrator complex subunit 11
P: PP2A-A
Q: PP2A-C
U: unknown
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,210,27816
Polymers1,210,03712
Non-polymers2414
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area65700 Å2
ΔGint-371 kcal/mol
Surface area364380 Å2

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Components

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Integrator complex subunit ... , 9 types, 9 molecules ABDEFGHIK

#1: Protein Integrator complex subunit 1 / / Int1


Mass: 244574.922 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS1, KIAA1440, UNQ1821/PRO3434 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q8N201
#2: Protein Integrator complex subunit 2 / / Int2


Mass: 134451.625 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS2, KIAA1287 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q9H0H0
#3: Protein Integrator complex subunit 4 / / Int4


Mass: 108306.758 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS4, MSTP093 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q96HW7
#4: Protein Integrator complex subunit 5 / / Int5


Mass: 108115.227 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS5, KIAA1698 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q6P9B9
#5: Protein Integrator complex subunit 6 / / Int6


Mass: 100527.078 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS6, DBI1, DDX26, DDX26A / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q9UL03
#6: Protein Integrator complex subunit 7 / / Int7


Mass: 106952.617 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS7, C1orf73 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q9NVH2
#7: Protein Integrator complex subunit 8 / / Int8


Mass: 113219.859 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS8, C8orf52 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q75QN2
#8: Protein Integrator complex subunit 9 / / Int9


Mass: 73891.219 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS9, RC74 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q9NV88
#9: Protein Integrator complex subunit 11 / / Int11


Mass: 67756.562 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS11, CPSF3L, RC68 / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
References: UniProt: Q5TA45, Hydrolases; Acting on ester bonds; Endoribonucleases producing 3'-phosphomonoesters

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Protein , 3 types, 3 molecules PQU

#10: Protein PP2A-A / PP2A subunit A isoform PR65-alpha / Serine/threonine-protein phosphatase 2A 65 kDa regulatory ...PP2A subunit A isoform PR65-alpha / Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform


Mass: 66034.883 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P30153
#11: Protein PP2A-C / PP2A-alpha / Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform


Mass: 35636.152 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: P67775, protein-serine/threonine phosphatase
#12: Protein unknown


Mass: 50570.449 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)

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Non-polymers , 2 types, 4 molecules

#13: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#14: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn

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Details

Has ligand of interestN
Sequence detailsFor chain U, the density of UNK residues is too cracked or discontinuous to assign fitable sequence.

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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

Component
IDNameTypeEntity IDParent-IDSource
1human Integrator-PP2A complexCOMPLEX#1-#120RECOMBINANT
2Integrator complex subunit 1, 2, 4, 5, 6, 7, 8, 9, 11COMPLEX#1-#91RECOMBINANT
3PP2AProtein phosphatase 2COMPLEX#10-#111RECOMBINANT
4unknown subunitCOMPLEX#121RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
44Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
22Homo sapiens (human)9606HEK239T
33Homo sapiens (human)9606HEK293T
44Homo sapiens (human)9606HEK293T
Buffer solutionpH: 7.4
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 FIELDBright-field microscopy
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 68378 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 47.99 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00258719
ELECTRON MICROSCOPYf_angle_d0.47880149
ELECTRON MICROSCOPYf_dihedral_angle_d6.87835741
ELECTRON MICROSCOPYf_chiral_restr0.0359734
ELECTRON MICROSCOPYf_plane_restr0.00310467

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