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- EMDB-33385: Cryo-EM structure of the histone methyltransferase SET8 bound to ... -

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Basic information

Entry
Database: EMDB / ID: EMD-33385
TitleCryo-EM structure of the histone methyltransferase SET8 bound to H4K20Ecx-nucleosome
Map data
Sample
  • Complex: Ternary complex of SET8 with H4K20Ecx nucleosome and SAM
    • Complex: Histone H3/H4/H2A/H2B
      • Protein or peptide: Histone H3
      • Protein or peptide: Histone H4
      • Protein or peptide: Histone H2A
      • Protein or peptide: Histone H2B 1.1
    • Complex: DNA
      • DNA: DNA (145-MER)
      • DNA: DNA (145-MER)
    • Complex: N-lysine methyltransferase KMT5A
      • Protein or peptide: N-lysine methyltransferase KMT5A
  • Ligand: S-ADENOSYLMETHIONINES-Adenosyl methionine
Function / homology
Function and homology information


histone H4K20 monomethyltransferase activity / lysine N-methyltransferase activity / [histone H4]-lysine20 N-methyltransferase / histone H4K20 methyltransferase activity / histone H4 methyltransferase activity / peptidyl-lysine monomethylation / polytene chromosome / protein-lysine N-methyltransferase activity / mitotic chromosome condensation / regulation of DNA damage response, signal transduction by p53 class mediator ...histone H4K20 monomethyltransferase activity / lysine N-methyltransferase activity / [histone H4]-lysine20 N-methyltransferase / histone H4K20 methyltransferase activity / histone H4 methyltransferase activity / peptidyl-lysine monomethylation / polytene chromosome / protein-lysine N-methyltransferase activity / mitotic chromosome condensation / regulation of DNA damage response, signal transduction by p53 class mediator / histone methyltransferase activity / negative regulation of double-strand break repair via homologous recombination / Transferases; Transferring one-carbon groups; Methyltransferases / Condensation of Prophase Chromosomes / regulation of signal transduction by p53 class mediator / Regulation of TP53 Activity through Methylation / PKMTs methylate histone lysines / structural constituent of chromatin / transcription corepressor activity / nucleosome / protein heterodimerization activity / cell division / negative regulation of DNA-templated transcription / chromatin / regulation of transcription by RNA polymerase II / negative regulation of transcription by RNA polymerase II / DNA binding / nucleoplasm / nucleus / cytosol
Similarity search - Function
Class V SAM-dependent methyltransferases / : / Histone-lysine N-methyltransferase (EC 2.1.1.43) family profile. / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily / SET domain / SET domain profile. / SET domain / Histone H2B signature. / Histone H2B ...Class V SAM-dependent methyltransferases / : / Histone-lysine N-methyltransferase (EC 2.1.1.43) family profile. / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily / SET domain / SET domain profile. / SET domain / Histone H2B signature. / Histone H2B / Histone H2B / Histone H2A conserved site / Histone H2A signature. / Histone H2A, C-terminal domain / C-terminus of histone H2A / Histone H2A / Histone 2A / Histone H3 signature 1. / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Histone-fold
Similarity search - Domain/homology
Histone H3 / Histone H2B 1.1 / Histone H2A / N-lysine methyltransferase KMT5A
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsShi LX / Zhou Z
Funding support China, 1 items
OrganizationGrant numberCountry
National Science Foundation (NSF, China) China
CitationJournal: FASEB J / Year: 2022
Title: Structural basis of nucleosomal H4K20 methylation by methyltransferase SET8.
Authors: Liuxin Shi / Li Huang / Haizhen Long / Aoqun Song / Zheng Zhou /
Abstract: Histone H4 lysine 20 monomethylation (H4K20me1) plays a crucial role in multiple processes including DNA damage repair, DNA replication, and cell cycle control. Histone methyltransferase SET8 ...Histone H4 lysine 20 monomethylation (H4K20me1) plays a crucial role in multiple processes including DNA damage repair, DNA replication, and cell cycle control. Histone methyltransferase SET8 (previously named PR-Set7/KMT5A) mediates the chromatin deposition of H4K20me1, but how SET8 recognizes and modifies H4 in the context of the nucleosome is not fully understood. Here, we developed a simple chemical modification approach for H4K20 substitution by using the lysine analog S-ethyl-L-cysteine (Ecx). Substitution of H4K20 with H4Ecx20 improves the stability of the SET8-nucleosome complex, allowing us to determine the cryo-EM structure at 3.2 Å resolution. Structural analyses show that SET8 directly interacts with the H4 tail and the H2A-H2B acidic patch to ensure nucleosome binding. SET8 residues R339, K341, K351 make contact with nucleosomal DNA at the super helical location 2 (SHL2). Substitution of SET8 DNA-binding residues with alanines decreases the SET8-nucleosome interaction and impairs the methyltransferase activity. Disrupting the binding between SET8 R192 and H2A-H2B acidic patch decreases the cellular level of H4K20me1. Together, these results reveal a near-atomic resolution structure of SET8-bound nucleosome and provide insights into the SET8-mediated H4K20 recognition and modification. The lysine-to-Ecx substitution approach can be applied to the study of other methyltransferases.
History
DepositionMay 6, 2022-
Header (metadata) releaseJun 1, 2022-
Map releaseJun 1, 2022-
UpdateJun 1, 2022-
Current statusJun 1, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33385.png

Downloads & links

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Map

FileDownload / File: emd_33385.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1 Å
Density
Contour LevelBy AUTHOR: 1.4
Minimum - Maximum-38.21829 - 61.698112
Average (Standard dev.)-6.1267957e-12 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 256.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_33385_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_33385_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Ternary complex of SET8 with H4K20Ecx nucleosome and SAM

EntireName: Ternary complex of SET8 with H4K20Ecx nucleosome and SAM
Components
  • Complex: Ternary complex of SET8 with H4K20Ecx nucleosome and SAM
    • Complex: Histone H3/H4/H2A/H2B
      • Protein or peptide: Histone H3
      • Protein or peptide: Histone H4
      • Protein or peptide: Histone H2A
      • Protein or peptide: Histone H2B 1.1
    • Complex: DNA
      • DNA: DNA (145-MER)
      • DNA: DNA (145-MER)
    • Complex: N-lysine methyltransferase KMT5A
      • Protein or peptide: N-lysine methyltransferase KMT5A
  • Ligand: S-ADENOSYLMETHIONINES-Adenosyl methionine

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Supramolecule #1: Ternary complex of SET8 with H4K20Ecx nucleosome and SAM

SupramoleculeName: Ternary complex of SET8 with H4K20Ecx nucleosome and SAM
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#7
Source (natural)Organism: Xenopus laevis (African clawed frog)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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Supramolecule #2: Histone H3/H4/H2A/H2B

SupramoleculeName: Histone H3/H4/H2A/H2B / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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Supramolecule #3: DNA

SupramoleculeName: DNA / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #5-#6
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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Supramolecule #4: N-lysine methyltransferase KMT5A

SupramoleculeName: N-lysine methyltransferase KMT5A / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #7

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Macromolecule #1: Histone H3

MacromoleculeName: Histone H3 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 15.30393 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
ARTKQTARKS TGGKAPRKQL ATKAARKSAP ATGGVKKPHR YRPGTVALRE IRRYQKSTEL LIRKLPFQRL VREIAQDFKT DLRFQSSAV MALQEASEAY LVALFEDTNL CAIHAKRVTI MPKDIQLARR IRGERA

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Macromolecule #2: Histone H4

MacromoleculeName: Histone H4 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 11.265247 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
SGRGKGGKGL GKGGAKRHR(ECX) VLRDNIQGIT KPAIRRLARR GGVKRISGLI YEETRGVLKV FLENVIRDAV TYTEHA KRK TVTAMDVVYA LKRQGRTLYG FGG

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Macromolecule #3: Histone H2A

MacromoleculeName: Histone H2A / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 13.978241 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
SGRGKQGGKT RAKAKTRSSR AGLQFPVGRV HRLLRKGNYA ERVGAGAPVY LAAVLEYLTA EILELAGNAA RDNKKTRIIP RHLQLAVRN DEELNKLLGR VTIAQGGVLP NIQSVLLPKK TESSKSAKSK

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Macromolecule #4: Histone H2B 1.1

MacromoleculeName: Histone H2B 1.1 / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 13.524752 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
AKSAPAPKKG SKKAVTKTQK KDGKKRRKTR KESYAIYVYK VLKQVHPDTG ISSKAMSIMN SFVNDVFERI AGEASRLAHY NKRSTITSR EIQTAVRLLL PGELAKHAVS EGTKAVTKYT SAK

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Macromolecule #7: N-lysine methyltransferase KMT5A

MacromoleculeName: N-lysine methyltransferase KMT5A / type: protein_or_peptide / ID: 7 / Number of copies: 1 / Enantiomer: LEVO
EC number: Transferases; Transferring one-carbon groups; Methyltransferases
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.349803 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGSSHHHHHH SSENLYFQGH MAKQALKKPI KGKQAPRKKA QGKTQQNRKL TDFYPVRRSS RKSKAELQSE ERKRIDELIE SGKEEGMKI DLIDGKGRGV IATKQFSRGD FVVEYHGDLI EITDAKKREA LYAQDPSTGC YMYYFQYLSK TYCVDATRET N RLGRLINH ...String:
MGSSHHHHHH SSENLYFQGH MAKQALKKPI KGKQAPRKKA QGKTQQNRKL TDFYPVRRSS RKSKAELQSE ERKRIDELIE SGKEEGMKI DLIDGKGRGV IATKQFSRGD FVVEYHGDLI EITDAKKREA LYAQDPSTGC YMYYFQYLSK TYCVDATRET N RLGRLINH SKCGNCQTKL HDIDGVPHLI LIASRDIAAG EELLYDYGDR SKASIEAHPW LKH

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Macromolecule #5: DNA (145-MER)

MacromoleculeName: DNA (145-MER) / type: dna / ID: 5 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.761523 KDa
SequenceString: (DA)(DT)(DC)(DA)(DC)(DA)(DA)(DT)(DC)(DC) (DC)(DG)(DG)(DT)(DG)(DC)(DC)(DG)(DA)(DG) (DG)(DC)(DC)(DG)(DC)(DT)(DC)(DA)(DA) (DT)(DT)(DG)(DG)(DT)(DC)(DG)(DT)(DA)(DG) (DA) (DC)(DA)(DG)(DC)(DT)(DC) ...String:
(DA)(DT)(DC)(DA)(DC)(DA)(DA)(DT)(DC)(DC) (DC)(DG)(DG)(DT)(DG)(DC)(DC)(DG)(DA)(DG) (DG)(DC)(DC)(DG)(DC)(DT)(DC)(DA)(DA) (DT)(DT)(DG)(DG)(DT)(DC)(DG)(DT)(DA)(DG) (DA) (DC)(DA)(DG)(DC)(DT)(DC)(DT)(DA) (DG)(DC)(DA)(DC)(DC)(DG)(DC)(DT)(DT)(DA) (DA)(DA) (DC)(DG)(DC)(DA)(DC)(DG)(DT) (DA)(DC)(DG)(DG)(DA)(DA)(DT)(DC)(DC)(DG) (DT)(DA)(DC) (DG)(DT)(DG)(DC)(DG)(DT) (DT)(DT)(DA)(DA)(DG)(DC)(DG)(DG)(DT)(DG) (DC)(DT)(DA)(DG) (DA)(DG)(DC)(DT)(DG) (DT)(DC)(DT)(DA)(DC)(DG)(DA)(DC)(DC)(DA) (DA)(DT)(DT)(DG)(DA) (DG)(DC)(DG)(DG) (DC)(DC)(DT)(DC)(DG)(DG)(DC)(DA)(DC)(DC) (DG)(DG)(DG)(DA)(DT)(DT) (DG)(DT)(DG) (DA)(DT)

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Macromolecule #6: DNA (145-MER)

MacromoleculeName: DNA (145-MER) / type: dna / ID: 6 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.752508 KDa
SequenceString: (DA)(DT)(DC)(DA)(DC)(DA)(DA)(DT)(DC)(DC) (DC)(DG)(DG)(DT)(DG)(DC)(DC)(DG)(DA)(DG) (DG)(DC)(DC)(DG)(DC)(DT)(DC)(DA)(DA) (DT)(DT)(DG)(DG)(DT)(DC)(DG)(DT)(DA)(DG) (DA) (DC)(DA)(DG)(DC)(DT)(DC) ...String:
(DA)(DT)(DC)(DA)(DC)(DA)(DA)(DT)(DC)(DC) (DC)(DG)(DG)(DT)(DG)(DC)(DC)(DG)(DA)(DG) (DG)(DC)(DC)(DG)(DC)(DT)(DC)(DA)(DA) (DT)(DT)(DG)(DG)(DT)(DC)(DG)(DT)(DA)(DG) (DA) (DC)(DA)(DG)(DC)(DT)(DC)(DT)(DA) (DG)(DC)(DA)(DC)(DC)(DG)(DC)(DT)(DT)(DA) (DA)(DA) (DC)(DG)(DC)(DA)(DC)(DG)(DT) (DA)(DC)(DG)(DG)(DA)(DT)(DT)(DC)(DC)(DG) (DT)(DA)(DC) (DG)(DT)(DG)(DC)(DG)(DT) (DT)(DT)(DA)(DA)(DG)(DC)(DG)(DG)(DT)(DG) (DC)(DT)(DA)(DG) (DA)(DG)(DC)(DT)(DG) (DT)(DC)(DT)(DA)(DC)(DG)(DA)(DC)(DC)(DA) (DA)(DT)(DT)(DG)(DA) (DG)(DC)(DG)(DG) (DC)(DC)(DT)(DC)(DG)(DG)(DC)(DA)(DC)(DC) (DG)(DG)(DG)(DA)(DT)(DT) (DG)(DT)(DG) (DA)(DT)

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Macromolecule #8: S-ADENOSYLMETHIONINE

MacromoleculeName: S-ADENOSYLMETHIONINE / type: ligand / ID: 8 / Number of copies: 1 / Formula: SAM
Molecular weightTheoretical: 398.437 Da
Chemical component information

ChemComp-SAM:
S-ADENOSYLMETHIONINE / S-Adenosyl methionine

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: DIFFRACTION / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.5 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2227867
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 262534

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