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- PDB-8eqv: Cryo-EM structure of PRC2 in complex with the long isoform of AEBP2 -

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Basic information

Entry
Database: PDB / ID: 8eqv
TitleCryo-EM structure of PRC2 in complex with the long isoform of AEBP2
Components
  • Histone-binding protein RBBP4
  • Histone-lysine N-methyltransferase EZH2
  • Polycomb protein EED
  • Polycomb protein SUZ12
  • Zinc finger protein AEBP2
KeywordsGENE REGULATION / Polycomb repressive complex 2 Histone methyltransferase
Function / homology
Function and homology information


hepatocyte homeostasis / cellular response to trichostatin A / regulation of gliogenesis / negative regulation of striated muscle cell differentiation / negative regulation of keratinocyte differentiation / [histone H3]-lysine27 N-trimethyltransferase / response to tetrachloromethane / regulation of kidney development / CAF-1 complex / negative regulation of retinoic acid receptor signaling pathway ...hepatocyte homeostasis / cellular response to trichostatin A / regulation of gliogenesis / negative regulation of striated muscle cell differentiation / negative regulation of keratinocyte differentiation / [histone H3]-lysine27 N-trimethyltransferase / response to tetrachloromethane / regulation of kidney development / CAF-1 complex / negative regulation of retinoic acid receptor signaling pathway / histone H3K27 trimethyltransferase activity / cerebellar cortex development / primary miRNA binding / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / histone H3K27 methyltransferase activity / random inactivation of X chromosome / sex chromatin / positive regulation of cell cycle G1/S phase transition / NURF complex / regulatory ncRNA-mediated heterochromatin formation / facultative heterochromatin formation / NuRD complex / regulation of cell fate specification / cardiac muscle hypertrophy in response to stress / negative regulation of stem cell population maintenance / DNA replication-dependent chromatin assembly / ESC/E(Z) complex / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / negative regulation of stem cell differentiation / regulation of stem cell differentiation / protein-lysine N-methyltransferase activity / RSC-type complex / Polo-like kinase mediated events / chromatin silencing complex / pronucleus / Transcription of E2F targets under negative control by DREAM complex / positive regulation of dendrite development / histone H3K9me2/3 reader activity / ATPase complex / histone H3 methyltransferase activity / G1 to G0 transition / histone methyltransferase activity / synaptic transmission, GABAergic / Regulation of PD-L1(CD274) transcription / DNA methylation-dependent constitutive heterochromatin formation / negative regulation of G1/S transition of mitotic cell cycle / G1/S-Specific Transcription / spinal cord development / lncRNA binding / negative regulation of gene expression, epigenetic / Sin3-type complex / positive regulation of MAP kinase activity / oligodendrocyte differentiation / histone deacetylase complex / positive regulation of stem cell population maintenance / positive regulation of protein serine/threonine kinase activity / Transcriptional Regulation by E2F6 / negative regulation of transcription elongation by RNA polymerase II / RNA Polymerase I Transcription Initiation / G0 and Early G1 / subtelomeric heterochromatin formation / positive regulation of GTPase activity / keratinocyte differentiation / negative regulation of cell differentiation / positive regulation of epithelial to mesenchymal transition / ribonucleoprotein complex binding / RNA polymerase II core promoter sequence-specific DNA binding / Cyclin E associated events during G1/S transition / pericentric heterochromatin / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / Cyclin A:Cdk2-associated events at S phase entry / nucleosome binding / Regulation of TP53 Activity through Acetylation / protein localization to chromatin / heterochromatin / negative regulation of cytokine production involved in inflammatory response / B cell differentiation / Deposition of new CENPA-containing nucleosomes at the centromere / liver regeneration / negative regulation of cell migration / stem cell differentiation / SUMOylation of chromatin organization proteins / transcription corepressor binding / Regulation of PTEN gene transcription / hippocampus development / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / PRC2 methylates histones and DNA / Regulation of endogenous retroelements by KRAB-ZFP proteins / Defective pyroptosis / transcription coregulator activity / HDACs deacetylate histones / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / negative regulation of transforming growth factor beta receptor signaling pathway / G1/S transition of mitotic cell cycle / promoter-specific chromatin binding / brain development / protein-DNA complex / chromatin DNA binding / regulation of circadian rhythm / Negative Regulation of CDH1 Gene Transcription
Similarity search - Function
: / : / AEBP2-like, C-terminal SH3 domain / : / Polycomb protein SUZ12-like, Zn domain / EZH2, SET domain / Polycomb protein, VEFS-Box / VEFS-Box of polycomb protein / Histone-lysine N-methyltransferase EZH1/EZH2 / Polycomb repressive complex 2 subunit EZH1/EZH2, tri-helical domain ...: / : / AEBP2-like, C-terminal SH3 domain / : / Polycomb protein SUZ12-like, Zn domain / EZH2, SET domain / Polycomb protein, VEFS-Box / VEFS-Box of polycomb protein / Histone-lysine N-methyltransferase EZH1/EZH2 / Polycomb repressive complex 2 subunit EZH1/EZH2, tri-helical domain / Pre-SET CXC domain / : / WD repeat binding protein EZH2 / Polycomb repressive complex 2 tri-helical domain / CXC domain / Ezh2, MCSS domain / Tesmin/TSO1-like CXC domain / Tesmin/TSO1-like CXC domain / CXC domain / Histone-lysine N-methyltransferase EZH1/2-like / CXC domain profile. / Histone-binding protein RBBP4, N-terminal / Histone-binding protein RBBP4 or subunit C of CAF1 complex / : / : / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain / SET domain profile. / SET domain superfamily / SET domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / zinc finger / Zinc finger C2H2 type domain profile. / Zinc finger C2H2 superfamily / Zinc finger C2H2 type domain signature. / Zinc finger C2H2-type / WD domain, G-beta repeat / 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
Similarity search - Domain/homology
Polycomb protein EED / Histone-binding protein RBBP4 / Polycomb protein SUZ12 / Histone-lysine N-methyltransferase EZH2 / Zinc finger protein AEBP2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.64 Å
AuthorsBoudes, M. / Zhang, Q. / Flanigan, S.F. / Davidovich, C.
Funding support Australia, 7items
OrganizationGrant numberCountry
Australian Research Council (ARC)DP190103407 Australia
Other privateSylvia and Charles Viertel Senior Medical Research Fellowship Australia
National Health and Medical Research Council (NHMRC, Australia)APP1162921 Australia
National Health and Medical Research Council (NHMRC, Australia)APP1184637 Australia
National Health and Medical Research Council (NHMRC, Australia)APP2011767 Australia
Australian Research Council (ARC)DE180100219 Australia
National Health and Medical Research Council (NHMRC, Australia)APP1196365 Australia
CitationJournal: EMBO J / Year: 2025
Title: Auto-inhibition of PRC2 by the broadly expressed long isoform of AEBP2.
Authors: Marlena Mucha / Zhihao Lai / Nicholas J McKenzie / Francesca Matrà / Marion Boudes / Sarena F Flanigan / Maria Teresa Alejo-Vinogradova / Craig Monger / Qi Zhang / Darragh Nimmo / Evan ...Authors: Marlena Mucha / Zhihao Lai / Nicholas J McKenzie / Francesca Matrà / Marion Boudes / Sarena F Flanigan / Maria Teresa Alejo-Vinogradova / Craig Monger / Qi Zhang / Darragh Nimmo / Evan Healy / Ademar J Silva / Daniel Angelov / David M Reck / Gráinne Holland / Zeynep Eda Atmaca / Helen E King / Maeve Hamilton / Eleanor Glancy / James Nolan / Robert J Weatheritt / Oliver Bell / Michiel Vermeulen / Chen Davidovich / Adrian P Bracken /
Abstract: Polycomb Repressive Complex 2 (PRC2) is an essential chromatin regulator responsible for mono-, di- and tri-methylating H3K27. Control of PRC2 activity is a critical process in development and ...Polycomb Repressive Complex 2 (PRC2) is an essential chromatin regulator responsible for mono-, di- and tri-methylating H3K27. Control of PRC2 activity is a critical process in development and disease, yet no inhibitory cofactor has been identified in somatic cells. Here, we show that the alternative isoforms of its accessory subunit AEBP2, namely AEBP2 (short) and AEBP2 (long), perform opposite functions in modulating PRC2 activity. Contrary to prior assumptions that AEBP2 enhances PRC2 function, we find that the widely expressed AEBP2 isoform inhibits it. AEBP2 is expressed throughout embryogenesis and adulthood and inhibits PRC2 DNA binding, histone methyltransferase activity, and binding to target genes. In contrast, AEBP2, expressed during early embryogenesis, promotes PRC2 DNA-binding activity and is essential for de novo repression of target genes during the transition from naïve to primed pluripotency. Mechanistically, through high-resolution cryo-EM and mutagenesis, we show that the recently evolved, negatively charged N-terminal region of AEBP2 inhibits PRC2. We propose a scenario in which the N-terminus of AEBP2 arose in vertebrates to restrain PRC2 activity in somatic cells.
History
DepositionOct 9, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 31, 2024Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone-binding protein RBBP4
C: Zinc finger protein AEBP2
E: Polycomb protein EED
D: Histone-lysine N-methyltransferase EZH2
B: Polycomb protein SUZ12


Theoretical massNumber of molelcules
Total (without water)321,1875
Polymers321,1875
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Histone-binding protein RBBP4 / Chromatin assembly factor 1 subunit C / CAF-1 subunit C / Chromatin assembly factor I p48 subunit / ...Chromatin assembly factor 1 subunit C / CAF-1 subunit C / Chromatin assembly factor I p48 subunit / CAF-I p48 / Nucleosome-remodeling factor subunit RBAP48 / Retinoblastoma-binding protein 4 / RBBP-4 / Retinoblastoma-binding protein p48


Mass: 47709.527 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RBBP4, RBAP48 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q09028
#2: Protein Zinc finger protein AEBP2 / Adipocyte enhancer-binding protein 2 / AE-binding protein 2


Mass: 54535.496 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AEBP2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q6ZN18
#3: Protein Polycomb protein EED / hEED / Embryonic ectoderm development protein / WD protein associating with integrin cytoplasmic ...hEED / Embryonic ectoderm development protein / WD protein associating with integrin cytoplasmic tails 1 / WAIT-1


Mass: 50267.691 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EED / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: O75530
#4: Protein Histone-lysine N-methyltransferase EZH2 / ENX-1 / Enhancer of zeste homolog 2 / Lysine N-methyltransferase 6


Mass: 85492.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EZH2, KMT6 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q15910, [histone H3]-lysine27 N-trimethyltransferase
#5: Protein Polycomb protein SUZ12 / Chromatin precipitated E2F target 9 protein / ChET 9 protein / Joined to JAZF1 protein / Suppressor ...Chromatin precipitated E2F target 9 protein / ChET 9 protein / Joined to JAZF1 protein / Suppressor of zeste 12 protein homolog


Mass: 83181.922 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SUZ12, CHET9, JJAZ1, KIAA0160 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q15022
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

ComponentName: Ternary complex of PRC2 with long isoform of AEBP2 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.5
Details: 200 mM NaCl, 20 mM HEPES pH 7.5, 1 mM TCEP, 0.01% NP-40
Buffer component
IDConc.NameFormulaBuffer-ID
1200 mMsodium chlorideNaCl1
220 mMHEPES1
31 mMTCEP1
40.01 %NP-401
SpecimenConc.: 2.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Prior to cryo-EM sample preparation, complexes were PEGylated at 0.9 mg/mL with 5 mM MS(PEG)4 Methyl-PEG-NHS-Ester (ThermoFisher Scientific) for 2 h at 4oC.
Specimen supportDetails: 0.24 mBar, 120 s, 10 mAmp / Grid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K / Details: Blotting 3 seconds

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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 / Nominal magnification: 105000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Quantum ER / Energyfilter slit width: 10 eV

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameVersionCategoryDetails (eV)
1crYOLO1.7.6particle selection
4CTFFIND4.1CTF correction
9PHENIXmodel refinement
10cryoSPARC3.3.2initial Euler assignmentab initio
11cryoSPARC3.3.2final Euler assignmentnon-uniform refinement
13cryoSPARC3.3.23D reconstructionnon-uniform refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 847067
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.64 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 45024 / Num. of class averages: 1 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00314306
ELECTRON MICROSCOPYf_angle_d0.64919378
ELECTRON MICROSCOPYf_dihedral_angle_d4.8691879
ELECTRON MICROSCOPYf_chiral_restr0.0432121
ELECTRON MICROSCOPYf_plane_restr0.0052499

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