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- PDB-7k36: Cryo-EM structure of STRIPAK complex -

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Basic information

Entry
Database: PDB / ID: 7k36
TitleCryo-EM structure of STRIPAK complex
Components
  • (Serine/threonine-protein phosphatase 2A ...) x 2
  • MOB-like protein phocein
  • Striatin-3
  • Striatin-interacting protein 1
KeywordsSIGNALING PROTEIN / phosphorylation / complex / PP2A
Function / homology
Function and homology information


armadillo repeat domain binding / meiotic spindle elongation / Integration of energy metabolism / PP2A-mediated dephosphorylation of key metabolic factors / RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity / MASTL Facilitates Mitotic Progression / protein phosphatase type 2A complex / protein serine/threonine phosphatase complex / peptidyl-threonine dephosphorylation ...armadillo repeat domain binding / meiotic spindle elongation / Integration of energy metabolism / PP2A-mediated dephosphorylation of key metabolic factors / RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity / MASTL Facilitates Mitotic Progression / protein phosphatase type 2A complex / protein serine/threonine phosphatase complex / peptidyl-threonine dephosphorylation / regulation of meiotic cell cycle process involved in oocyte maturation / mitotic sister chromatid separation / meiotic sister chromatid cohesion, centromeric / INTAC complex / RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity / FAR/SIN/STRIPAK complex / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / negative regulation of intracellular estrogen receptor signaling pathway / Inhibition of replication initiation of damaged DNA by RB1/E2F1 / female meiotic nuclear division / protein phosphatase regulator activity / GABA receptor binding / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / protein antigen binding / ERKs are inactivated / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / 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 / RNA polymerase II transcription initiation surveillance / Co-stimulation by CD28 / regulation of cell morphogenesis / regulation of growth / Disassembly of the destruction complex and recruitment of AXIN to the membrane / cortical actin cytoskeleton organization / negative regulation of epithelial to mesenchymal transition / Golgi cisterna membrane / Co-inhibition by CTLA4 / Platelet sensitization by LDL / protein-serine/threonine phosphatase / negative regulation of glycolytic process through fructose-6-phosphate / positive regulation of NLRP3 inflammasome complex assembly / ERK/MAPK targets / protein serine/threonine phosphatase activity / mesoderm development / vascular endothelial cell response to oscillatory fluid shear stress / T cell homeostasis / regulation of cell differentiation / regulation of microtubule polymerization / phosphoprotein phosphatase activity / regulation of G1/S transition of mitotic cell cycle / lateral plasma membrane / chromosome, centromeric region / DARPP-32 events / negative regulation of hippo signaling / protein dephosphorylation / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / Cyclin A/B1/B2 associated events during G2/M transition / spindle assembly / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / cytoskeleton organization / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Mitotic Prometaphase / Recruitment of mitotic centrosome proteins and complexes / EML4 and NUDC in mitotic spindle formation / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Recruitment of NuMA to mitotic centrosomes / protein tyrosine phosphatase activity / Anchoring of the basal body to the plasma membrane / protein phosphatase 2A binding / Resolution of Sister Chromatid Cohesion / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / AURKA Activation by TPX2 / meiotic cell cycle / chromosome segregation / RAF activation / Spry regulation of FGF signaling / RHO GTPases Activate Formins / negative regulation of canonical Wnt signaling pathway / PKR-mediated signaling / Degradation of beta-catenin by the destruction complex / response to lead ion / small GTPase binding / tau protein binding / spindle pole / Negative regulation of MAPK pathway / Cyclin D associated events in G1 / Separation of Sister Chromatids / Regulation of TP53 Degradation / Regulation of PLK1 Activity at G2/M Transition / response to estradiol / mitotic cell cycle / microtubule cytoskeleton
Similarity search - Function
Far11/STRP, N-terminal / Far11/STRP, C-terminal / Far11/STRP / N1221-like protein / Domain of unknown function (DUF3402) / N1221-like protein / Domain of unknown function (DUF3402) / Striatin, N-terminal / : / Striatin family ...Far11/STRP, N-terminal / Far11/STRP, C-terminal / Far11/STRP / N1221-like protein / Domain of unknown function (DUF3402) / N1221-like protein / Domain of unknown function (DUF3402) / Striatin, N-terminal / : / Striatin family / MOB kinase activator / MOB kinase activator family / MOB kinase activator superfamily / Mob1/phocein family / Mob1/phocein 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 / Metallo-dependent phosphatases / Purple Acid Phosphatase; chain A, domain 2 / Butyryl-CoA Dehydrogenase, subunit A; domain 3 / Calcineurin-like phosphoesterase domain, ApaH type / Calcineurin-like phosphoesterase / Leucine-rich Repeat Variant / Leucine-rich Repeat Variant / Metallo-dependent phosphatase-like / 4-Layer Sandwich / Armadillo-like helical / Alpha Horseshoe / WD domain, G-beta repeat / Armadillo-type fold / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Up-down Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
INOSITOL HEXAKISPHOSPHATE / : / Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform / Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform / Striatin-3 / Striatin-interacting protein 1 / MOB-like protein phocein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsJeong, B.-C. / Bai, X.C.
Funding support United States, 5items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM132275 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)CA220283 United States
Welch FoundationI-1932 United States
Welch FoundationI-1944 United States
Welch FoundationI-1702 United States
CitationJournal: Nat Struct Mol Biol / Year: 2021
Title: Cryo-EM structure of the Hippo signaling integrator human STRIPAK.
Authors: Byung-Cheon Jeong / Sung Jun Bae / Lisheng Ni / Xuewu Zhang / Xiao-Chen Bai / Xuelian Luo /
Abstract: The striatin-interacting phosphatase and kinase (STRIPAK) complex is a large, multisubunit protein phosphatase 2A (PP2A) assembly that integrates diverse cellular signals in the Hippo pathway to ...The striatin-interacting phosphatase and kinase (STRIPAK) complex is a large, multisubunit protein phosphatase 2A (PP2A) assembly that integrates diverse cellular signals in the Hippo pathway to regulate cell proliferation and survival. The architecture and assembly mechanism of this critical complex are poorly understood. Using cryo-EM, we determine the structure of the human STRIPAK core comprising PP2AA, PP2AC, STRN3, STRIP1, and MOB4 at 3.2-Å resolution. Unlike the canonical trimeric PP2A holoenzyme, STRIPAK contains four copies of STRN3 and one copy of each the PP2AA-C heterodimer, STRIP1, and MOB4. The STRN3 coiled-coil domains form an elongated homotetrameric scaffold that links the complex together. An inositol hexakisphosphate (IP) is identified as a structural cofactor of STRIP1. Mutations of key residues at subunit interfaces disrupt the integrity of STRIPAK, causing aberrant Hippo pathway activation. Thus, STRIPAK is established as a noncanonical PP2A complex with four copies of regulatory STRN3 for enhanced signal integration.
History
DepositionSep 10, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 10, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 24, 2021Group: 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 1.2Mar 6, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type

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Structure visualization

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  • Deposited structure unit
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  • Superimposition on EM map
  • EMDB-22650
  • Imaged by UCSF Chimera
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Structure viewerMolecule:
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Assembly

Deposited unit
A: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform
B: Striatin-3
C: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
D: Striatin-3
E: Striatin-3
F: Striatin-3
G: Striatin-3
H: MOB-like protein phocein
I: Striatin-interacting protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)612,84314
Polymers611,9429
Non-polymers9015
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area23420 Å2
ΔGint-166 kcal/mol
Surface area92870 Å2

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Components

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

#1: Protein Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform / Medium tumor antigen-associated 61 kDa protein / PP2A subunit A isoform PR65-alpha / PP2A subunit A ...Medium tumor antigen-associated 61 kDa protein / PP2A subunit A isoform PR65-alpha / PP2A subunit A isoform R1-alpha


Mass: 65378.344 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPP2R1A / Details (production host): pBIG / Cell line (production host): High Five / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P30153
#3: Protein Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform / PP2A-alpha / Replication protein C / RP-C


Mass: 35636.152 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPP2CA / Details (production host): pBIG / Cell line (production host): High Five / Production host: Baculovirus expression vector pFastBac1-HM
References: UniProt: P67775, protein-serine/threonine phosphatase

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Protein , 3 types, 7 molecules BDEFGHI

#2: Protein
Striatin-3 / Cell cycle autoantigen SG2NA / S/G2 antigen


Mass: 77833.484 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: STRN3, GS2NA, SG2NA / Details (production host): pBIG / Cell line (production host): High Five / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: Q13033
#4: Protein MOB-like protein phocein / 2C4D / Class II mMOB1 / Mob1 homolog 3 / Mob3 / Mps one binder kinase activator-like 3 / ...2C4D / Class II mMOB1 / Mob1 homolog 3 / Mob3 / Mps one binder kinase activator-like 3 / Preimplantation protein 3


Mass: 26064.447 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MOB4, MOB3, MOBKL3, PHOCN, PREI3, CGI-95 / Details (production host): pBIG / Cell line (production host): High Five / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: Q9Y3A3
#5: Protein Striatin-interacting protein 1 / Protein FAM40A


Mass: 95695.656 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: STRIP1, FAM40A, KIAA1761 / Details (production host): pBIG / Cell line (production host): High Five / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: Q5VSL9

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Non-polymers , 3 types, 5 molecules

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


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn
#7: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#8: Chemical ChemComp-IHP / INOSITOL HEXAKISPHOSPHATE / MYO-INOSITOL HEXAKISPHOSPHATE / INOSITOL 1,2,3,4,5,6-HEXAKISPHOSPHATE


Mass: 660.035 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H18O24P6

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Details

Has ligand of interestN

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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

ComponentName: SK7 complex / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightValue: 0.8178 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Baculovirus expression vector pFastBac1-HM / Strain: High Five / Plasmid: pBIG1a
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
120 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidHEPES1
2100 mMSodium ChlorideNaCl1
31 mMtris(2-carboxyethyl)phosphineTCEP1
42 mMMagnesium ChlorideMgCl21
50.005 %4-Nonylphenyl-polyethylene glycolNP-401
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: The grid was coated with gold prior to use / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 FIELD / Calibrated magnification: 59524 X / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 64 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 4356
Image scansMovie frames/image: 32

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Processing

EM software
IDNameVersionCategory
1RELION3particle selection
2SerialEMimage acquisition
4GctfCTF correction
7UCSF Chimera1.14model fitting
10RELION3final Euler assignment
11RELION3classification
12RELION33D reconstruction
13PHENIX1.17.1_3660model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2451582
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 87779 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: REAL
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
12NPP

2npp

12NPP1PDBexperimental model
24N6J

4n6j

14N6J2PDBexperimental model
32YMU

2ymu

12YMU3PDBexperimental model
45YF4

5yf4

15YF44PDBexperimental model

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