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- PDB-8rc4: Structure of Integrator-PP2A complex -

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Basic information

Entry
Database: PDB / ID: 8rc4
TitleStructure of Integrator-PP2A complex
Components
  • (Integrator complex subunit ...) x 13
  • (Serine/threonine-protein phosphatase 2A ...) x 2
  • DSS1
KeywordsTRANSCRIPTION / Integrator complex / Post-termination complex / RNA Polymerase II / Pol II / RNAPII
Function / homology
Function and homology information


U2 snRNA 3'-end processing / regulation of fertilization / meiotic spindle elongation / Integration of energy metabolism / PP2A-mediated dephosphorylation of key metabolic factors / snRNA 3'-end processing / MASTL Facilitates Mitotic Progression / regulation of meiotic cell cycle process involved in oocyte maturation / mitotic sister chromatid separation / protein phosphatase type 2A complex ...U2 snRNA 3'-end processing / regulation of fertilization / meiotic spindle elongation / Integration of energy metabolism / PP2A-mediated dephosphorylation of key metabolic factors / snRNA 3'-end processing / 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 / snRNA processing / peptidyl-serine dephosphorylation / protein localization to nuclear envelope / 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 / regulation of transcription elongation by RNA polymerase II / GABA receptor binding / protein phosphatase regulator activity / protein antigen binding / flagellated sperm motility / integrator complex / 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 / 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 / Co-stimulation by CD28 / regulation of growth / Disassembly of the destruction complex and recruitment of AXIN to the membrane / centrosome localization / negative regulation of epithelial to mesenchymal transition / inner cell mass cell proliferation / 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 / RNA polymerase II transcribes snRNA genes / chromosome, centromeric region / DARPP-32 events / 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 / embryo implantation / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / RNA endonuclease activity / 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 / regulation of mitotic cell cycle / DNA damage checkpoint signaling / AURKA Activation by TPX2 / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / mitotic spindle organization / meiotic cell cycle / cellular response to ionizing radiation / chromosome segregation / negative regulation of transforming growth factor beta receptor signaling pathway
Similarity search - Function
Domain of unknown function DUF3677 / Integrator complex subunit 2, metazoa / Integrator complex subunit 2 / Integrator complex subunit 7 / Integrator complex subunit 1 / : / : / : / : / : ...Domain of unknown function DUF3677 / Integrator complex subunit 2, metazoa / Integrator complex subunit 2 / Integrator complex subunit 7 / Integrator complex subunit 1 / : / : / : / : / : / : / Integrator complex subunit 1, RP2B-binding domain / Integrator complex subunit 2 / Integrator complex subunit 1, R3 domain / Integrator complex subunit 1, R4 domain / Integrator complex subunit 1, INTS2-binding domain / Integrator complex subunit 7, C-terminal domain / Integrator complex subunit 7, N-terminal / Integrator complex subunit 7 helical bundle / Integrator complex subunit 10 / Integrator complex subunit 15 / INTS6/SAGE1/DDX26B/CT45, C-terminal / Integrator complex subunit 14 / Integrator complex subunit 14, beta-barrel domain / Integrator complex subunit 14, C-terminal / : / Integrator complex subunit 15 / INTS6/SAGE1/DDX26B/CT45 C-terminus / Integrator complex subunit 14, beta-barrel domain / Integrator complex subunit 14, alpha-helical domain / Integrator subunit 10 / Cell cycle regulator Mat89Bb / Cell cycle and development regulator Mat89Bb / Integrator complex subunit 5, C-terminal / Integrator complex subunit 5, N-terminal / Integrator complex subunit 8 / Integrator complex subunit 5 / Integrator complex subunit 5 N-terminus / Integrator complex subunit 5 C-terminus / : / INTS4 8 helical bundle domain / Sister chromatid cohesion protein PDS5 protein / Integrator complex subunit 9 / : / Integrator IntS9, C-terminal domain / Integrator complex subunit 11, MBL-fold / : / Integrator IntS11, C-terminal domain / 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 / : / 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 / 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 / Ribonuclease Z/Hydroxyacylglutathione hydrolase-like / von Willebrand factor A-like domain superfamily / 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 15 / Integrator complex subunit 14 ...: / 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 15 / Integrator complex subunit 14 / Integrator complex subunit 2 / Integrator complex subunit 9 / Integrator complex subunit 7 / Integrator complex subunit 13 / Integrator complex subunit 10 / Integrator complex subunit 6
Similarity search - Component
Biological speciesHomo sapiens (human)
Trichoplusia ni (cabbage looper)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsFianu, I. / Ochmann, M. / Walshe, J.L. / Cramer, P.
Funding support Germany, European Union, 3items
OrganizationGrant numberCountry
German Research Foundation (DFG)SFB860 Germany
German Research Foundation (DFG)SFB1565 Germany
European Research Council (ERC)EXC 2067/1-390729940European Union
CitationJournal: Nature / Year: 2024
Title: Structural basis of Integrator-dependent RNA polymerase II termination.
Authors: Isaac Fianu / Moritz Ochmann / James L Walshe / Olexandr Dybkov / Joseph Neos Cruz / Henning Urlaub / Patrick Cramer /
Abstract: The Integrator complex can terminate RNA polymerase II (Pol II) in the promoter-proximal region of genes. Previous work has shed light on how Integrator binds to the paused elongation complex ...The Integrator complex can terminate RNA polymerase II (Pol II) in the promoter-proximal region of genes. Previous work has shed light on how Integrator binds to the paused elongation complex consisting of Pol II, the DRB sensitivity-inducing factor (DSIF) and the negative elongation factor (NELF) and how it cleaves the nascent RNA transcript, but has not explained how Integrator removes Pol II from the DNA template. Here we present three cryo-electron microscopy structures of the complete Integrator-PP2A complex in different functional states. The structure of the pre-termination complex reveals a previously unresolved, scorpion-tail-shaped INTS10-INTS13-INTS14-INTS15 module that may use its 'sting' to open the DSIF DNA clamp and facilitate termination. The structure of the post-termination complex shows that the previously unresolved subunit INTS3 and associated sensor of single-stranded DNA complex (SOSS) factors prevent Pol II rebinding to Integrator after termination. The structure of the free Integrator-PP2A complex in an inactive closed conformation reveals that INTS6 blocks the PP2A phosphatase active site. These results lead to a model for how Integrator terminates Pol II transcription in three steps that involve major rearrangements.
History
DepositionDec 6, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 7, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 10, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2May 15, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 16, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
p: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform
q: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
r: DSS1
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
m: Integrator complex subunit 13
j: Integrator complex subunit 10
n: Integrator complex subunit 14
o: Integrator complex subunit 15
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,435,16520
Polymers1,434,92416
Non-polymers2414
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Serine/threonine-protein phosphatase 2A ... , 2 types, 2 molecules pq

#1: Protein Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform


Mass: 65579.531 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPP2R1A / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P30153
#2: Protein Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform


Mass: 35836.348 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPP2CA / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P67775

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Protein/peptide , 1 types, 1 molecules r

#3: Protein/peptide DSS1


Mass: 3753.969 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Trichoplusia ni (cabbage looper)

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Integrator complex subunit ... , 13 types, 13 molecules abdefghikmjno

#4: Protein Integrator complex subunit 1


Mass: 244776.078 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q8N201
#5: 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 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9H0H0
#6: 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 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q96HW7
#7: Protein Integrator complex subunit 5


Mass: 108316.422 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS5 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q6P9B9
#8: Protein Integrator complex subunit 6


Mass: 101166.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS6 / Production host: Trichoplusia (butterflies/moths) / References: UniProt: Q9UL03
#9: Protein Integrator complex subunit 7


Mass: 107153.805 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS7 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9NVH2
#10: Protein Integrator complex subunit 8 / Int8 / Protein kaonashi-1


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 / Production host: Trichoplusia (butterflies/moths) / References: UniProt: Q75QN2
#11: Protein Integrator complex subunit 9 / Int9 / Protein related to CPSF subunits of 74 kDa / RC-74


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 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9NV88
#12: Protein Integrator complex subunit 11


Mass: 67956.750 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS11 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q5TA45
#13: Protein Integrator complex subunit 13 / Cell cycle regulator Mat89Bb homolog / Germ cell tumor 1 / Protein asunder homolog / Sarcoma antigen NY-SAR-95


Mass: 80345.180 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS13, ASUN, C12orf11, GCT1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9NVM9
#14: Protein Integrator complex subunit 10 / Int10


Mass: 82339.867 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS10, C8orf35 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9NVR2
#15: Protein Integrator complex subunit 14 / von Willebrand factor A domain-containing protein 9


Mass: 57526.547 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS14, C15orf44, VWA9 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q96SY0
#16: Protein Integrator complex subunit 15


Mass: 50303.582 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INTS15 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q96N11

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Non-polymers , 2 types, 4 molecules

#17: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn / Feature type: SUBJECT OF INVESTIGATION
#18: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION

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Details

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

Component
IDNameTypeDetailsEntity IDParent-IDSource
1Integrator-PP2A complexCOMPLEXIntegrator, PP2A#1-#160MULTIPLE SOURCES
2Integrator-PP2A complexCOMPLEX#1-#2, #4-#161RECOMBINANT
3DSS1COMPLEX#31NATURAL
Molecular weightValue: 1.5 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Trichoplusia ni (cabbage looper)7111
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
SpecimenConc.: 0.3 mg/ml / Embedding 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: OTHER
Electron lensMode: OTHER / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 40.49 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 2335349 / Symmetry type: POINT
Atomic model buildingPDB-ID: 8RBX

8rbx


Accession code: 8RBX / Source name: PDB / Type: experimental model

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