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- EMDB-76889: PRC2(EZH2 S21A) AJ106-350 in the compact active state -

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Basic information

Entry
Database: EMDB / ID: EMD-76889
TitlePRC2(EZH2 S21A) AJ106-350 in the compact active state
Map data
Sample
  • Complex: Polycomb Repressive Complex 2
    • Protein or peptide: Polycomb Repressive Complex 2
KeywordsPRC2 / Polycomb / EZH2 / DNA BINDING PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsMatyas MN / Kasinath V / Lewis PW
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
National Science Foundation (NSF, United States) United States
CitationJournal: bioRxiv / Year: 2026
Title: EZH2 Serine 21 Phosphorylation Restrains Compact-State PRC2 Activation and H3K27me3 Propagation.
Authors: Andrew Q Rashoff / Mark Matyas / Elizabeth G Porter / Ryen Hazzard / Benjamin A Garcia / Vignesh Kasinath / Peter W Lewis
Abstract: Polycomb Repressive Complex 2 (PRC2) propagates H3K27me3 through EED-dependent allosteric activation, yet how cells modulate the magnitude of this positive-feedback response remains poorly understood. ...Polycomb Repressive Complex 2 (PRC2) propagates H3K27me3 through EED-dependent allosteric activation, yet how cells modulate the magnitude of this positive-feedback response remains poorly understood. Here, we identify phosphorylation of EZH2 serine 21 as a post-translational mechanism that attenuates PRC2 allosteric responsiveness. Prior structural studies have established that activator-bound PRC2 adopts both compact and extended active conformations. Using cryo-EM classification of wild-type and phospho-null EZH2 S21A PRC2 complexes, we find that the phospho-null EZH2 S21A substitution changes the distribution of particles across these pre-existing states, shifting PRC2 from a predominantly extended conformation to one enriched for the compact, allosterically activated conformation. Consistent with this structural transition, EZH2 S21A increases basal PRC2 activity, lowers the EC for H3K27me3-dependent stimulation, and accelerates H3K27me3 accumulation on peptide and nucleosome substrates. Disruption of the EED-EZH2 interface suppresses the S21A gain-of-activity phenotype, indicating that S21 phosphorylation constrains PRC2 by limiting productive EED-EZH2 allosteric coupling. In mesenchymal stem cells, loss of this phosphorylation-dependent restraint broadens H3K27me3 domains, reduces canonical PRC1 enrichment at high-occupancy Polycomb target loci, misregulates lineage-associated transcriptional programs, and impairs differentiation. These findings identify EZH2 S21 phosphorylation as a molecular rheostat that limits compact-state PRC2 activation, constrains H3K27me3 spreading, and preserves Polycomb-dependent developmental competence.
History
DepositionApr 24, 2026-
Header (metadata) releaseJul 1, 2026-
Map releaseJul 1, 2026-
UpdateJul 1, 2026-
Current statusJul 1, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_76889.png

Downloads & links

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Map

FileDownload / File: emd_76889.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.76 Å/pix.
x 384 pix.
= 289.958 Å		0.76 Å/pix.
x 384 pix.
= 289.958 Å		0.76 Å/pix.
x 384 pix.
= 289.958 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.7551 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0248
Minimum - Maximum-0.2172971 - 0.4411714
Average (Standard dev.)-0.0000840496 (±0.010793889)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 289.9584 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_76889_additional_1.map
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Half map: #2

Fileemd_76889_half_map_1.map
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Half map: #1

Fileemd_76889_half_map_2.map
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Sample components

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Entire : Polycomb Repressive Complex 2

EntireName: Polycomb Repressive Complex 2
Components
  • Complex: Polycomb Repressive Complex 2
    • Protein or peptide: Polycomb Repressive Complex 2

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Supramolecule #1: Polycomb Repressive Complex 2

SupramoleculeName: Polycomb Repressive Complex 2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 308 KDa

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Macromolecule #1: Polycomb Repressive Complex 2

MacromoleculeName: Polycomb Repressive Complex 2 / type: protein_or_peptide / ID: 1 / Enantiomer: DEXTRO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: GQTGKKSEKG PVCWRKRVKS EYMRLRQLKR FRRADEVKSM FSSNRQKILE RTEILNQEWK QRRIQPVHIL TSVSSLRGTR ECSVTSDLDF PTQVIPLKTL NAVASVPIMY SWSPLQQNFM VEDETVLHNI PYMGDEVLDQ DGTFIEELIK NYDGKVHGDR ECGFINDEIF ...String:
GQTGKKSEKG PVCWRKRVKS EYMRLRQLKR FRRADEVKSM FSSNRQKILE RTEILNQEWK QRRIQPVHIL TSVSSLRGTR ECSVTSDLDF PTQVIPLKTL NAVASVPIMY SWSPLQQNFM VEDETVLHNI PYMGDEVLDQ DGTFIEELIK NYDGKVHGDR ECGFINDEIF VELVNALGQY NDDDDDDDGD DPEEREEKQK DLEDHRDDKE SRPPRKFPSD KIFEAISSMF PDKGTAEELK EKYKELTEQQ LPGALPPECT PNIDGPNAKS VQREQSLHSF HTLFCRRCFK YDCFLHRKCN YSFHATPNTY KRKNTETALD NKPCGPQCYQ HLEGAKEFAA ALTAERIKTP PKRPGGRRRG RLPNNSSRPS TPTINVLESK DTDSDREAGT ETGGENNDKE EEEKKDETSS SSEANSRCQT PIKMKPNIEP PENVEWSGAE ASMFRVLIGT YYDNFCAIAR LIGTKTCRQV YEFRVKESSI IAPAPAEDVD TPPRKKKRKH RLWAAHCRKI QLKKDGSSNH VYNYQPCDHP RQPCDSSCPC VIAQNFCEKF CQCSSECQNR FPGCRCKAQC NTKQCPCYLA VRECDPDLCL TCGAADHWDS KNVSCKNCSI QRGSKKHLLL APSDVAGWGI FIKDPVQKNE FISEYCGEII SQDEADRRGK VYDKYMCSFL FNLNNDFVVD ATRKGNKIRF ANHSVNPNCY AKVMMVNGDH RIGIFAKRAI QTGEELFFDY RYSQADALKY VGIEREMEIP MADKEAAFD DAVEERVINE EYKIWKKNTP FLYDLVMTHA LEWPSLTAQW LPDVTRPEGK DFSIHRLVLG THTSDEQNHL VIASVQLPND DAQFDASHYD SEKGEFGGFG SVSGKIEIEI KINHEGEVNR ARYMPQNPCI IATKTPSSDV LVFDYTKHPS KPDPSGECNP DLRLRGHQKE GYGLSWNPNL SGHLLSASDD HTICLWDISA VPKEGKVVDA KTIFTGHTAV VEDVSWHLLH ESLFGSVADD QKLMIWDTRS NNTSKPSHSV DAHTAEVNCL SFNPYSEFIL ATGSADKTVA LWDLRNLKLK LHSFESHKDE IFQVQWSPHN ETILASSGTD RRLNVWDLSK IGEEQSPEDA EDGPPELLFI HGGHTAKISD FSWNPNEPWV ICSVSEDNIM QVWQMAENIY NDEDPEGSVD PEGQGS SSD GEPLSRMDSE DSISSTIMDV DSTISSGRST PAMMNGQGST TSSSKNIAYN CCWDQCQACF NSSPDLADHI RSIHVDGQRG GVFVCLWKGC KVYNTPSTSQ SWLQRHMLTH SGDKPFKCVV GGCNASFASQ GGLARHVPTH FSQQNSSKVS SQPKAKEESP SKAGMNKRRK LKNKRRRSLP RPHDFFDAQT LDAIRHRAIC FNLSAHIESL GKGHSVVFHS TVIAKRKEDS GKIKLLLHWM PEDILPDVWV NESERHQLKT KVVHLSKLPK DTALLLDPNI YRTMPQKRLK R VLPVKKPK MEHVQADHEL FLQAFEKPTQ IYRFLRTRNL IAPIFLHRTL TYMSHRNSRT NIKRKTFKVD DMLSKVEKMK GEQESHSLSA HLQLTFTGFF HKNDKPSPNS ENEQNSVTLE VLLVKVCHKK RKDVSCPIRQ VPTGKKQVPL NPDLNQTKPG NFPSLAVSSN EFEPSNSHMV KSYSLLFRVT RPGRREFNGM INGETNENID VNEELPARRK RNREDGEKTF VAQMTVFDKN RRLQLLDGEY EVAMQEMEEC PISKKRATWE TILDGKRLPP FETFSQGPTL QFTLRWTGET NDKSTAPIAK PLATRNSESL HQENKPGSVK PTQTIAVKES LTTDLQTRKE KDTPNENRQK LRIFYQFLYN NNTRQQTEAR DDLHCPWCTL NCRKLYSLLK HLKLCHSRFI FNYVYHPKGA RIDVSINECY DGSYAGNPQD IHRQPGFAFS RNGPVKRTPI THILVCRPKR TKASMSEFLE SEDGEVEQQR TYSSGHNRLY FHSDTCLPLR PQEMEVDSED EKDPEWLREK TITQIEEFSD VNEGEKEVMK LWNLHVMKHG FIADNQMNHA CMLFVENYGQ KIIKKNLCRN FMLHLVSMHD FNLISIMSID KAVTKLREMQ ARKRPRLQA QRKFAQSQPN SPSTTPVKIV EPLLPPPATQ ISDLSKRKPK TEDFLTFLCL RGSPALPNSM VYFGSSQDEE EVEEEDDETE DVKTATNNAS SSCQSTPRKG KTHKHVHNGH VFNGSSRSTR EKEPVQKHKS KEATPAKEKH SDHRADSRRE QASANHPAAA PSTGSSAKGL AATHHHPPLH RSAQDLRKQV SKVNGVTRMS SLGAGVTSAK KMREVRPSPS KTVKYTATVT KGAVTYT

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1 mg/mL
BufferpH: 7.9 / Component - Concentration: 150.0 mM / Component - Formula: NaCl / Component - Name: sodium chloride / Details: 150 mM NaCl, 25 mM HEPES, 1mM TCEP, 10% glycerol
GridModel: Quantifoil R2/1 / Material: GOLD / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Support film - Film thickness: 1.5 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 5.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC / Type: NONE
Startup modelType of model: EMDB MAP
EMDB ID:

7334

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 216043
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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