Journal: Nucleic Acids Res / Year: 2020 Title: The topology of chromatin-binding domains in the NuRD deacetylase complex. Authors: Christopher J Millard / Louise Fairall / Timothy J Ragan / Christos G Savva / John W R Schwabe / Abstract: Class I histone deacetylase complexes play essential roles in many nuclear processes. Whilst they contain a common catalytic subunit, they have diverse modes of action determined by associated ...Class I histone deacetylase complexes play essential roles in many nuclear processes. Whilst they contain a common catalytic subunit, they have diverse modes of action determined by associated factors in the distinct complexes. The deacetylase module from the NuRD complex contains three protein domains that control the recruitment of chromatin to the deacetylase enzyme, HDAC1/2. Using biochemical approaches and cryo-electron microscopy, we have determined how three chromatin-binding domains (MTA1-BAH, MBD2/3 and RBBP4/7) are assembled in relation to the core complex so as to facilitate interaction of the complex with the genome. We observe a striking arrangement of the BAH domains suggesting a potential mechanism for binding to di-nucleosomes. We also find that the WD40 domains from RBBP4 are linked to the core with surprising flexibility that is likely important for chromatin engagement. A single MBD2 protein binds asymmetrically to the dimerisation interface of the complex. This symmetry mismatch explains the stoichiometry of the complex. Finally, our structures suggest how the holo-NuRD might assemble on a di-nucleosome substrate.
History
Deposition
Oct 14, 2020
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Header (metadata) release
Nov 11, 2020
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Map release
Nov 11, 2020
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Update
May 1, 2024
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Current status
May 1, 2024
Processing site: PDBe / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Entire : Core NuRD deacetylase complex containing two copies of MTA1 and H...
Entire
Name: Core NuRD deacetylase complex containing two copies of MTA1 and HDAC1 and a single copy of MBD2
Components
Complex: Core NuRD deacetylase complex containing two copies of MTA1 and HDAC1 and a single copy of MBD2
Protein or peptide: Methyl-CpG-binding domain protein 2
Protein or peptide: Metastasis-associated protein MTA1
Protein or peptide: Histone deacetylase 1HDAC1
Ligand: INOSITOL HEXAKISPHOSPHATEPhytic acid
Ligand: ZINC ION
Ligand: POTASSIUM IONPotassium
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Supramolecule #1: Core NuRD deacetylase complex containing two copies of MTA1 and H...
Supramolecule
Name: Core NuRD deacetylase complex containing two copies of MTA1 and HDAC1 and a single copy of MBD2 type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)
Organism: Homo sapiens (human)
Molecular weight
Theoretical: 170 KDa
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Macromolecule #1: Methyl-CpG-binding domain protein 2
Macromolecule
Name: Methyl-CpG-binding domain protein 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Name: ZINC ION / type: ligand / ID: 5 / Number of copies: 2 / Formula: ZN
Molecular weight
Theoretical: 65.409 Da
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Macromolecule #6: POTASSIUM ION
Macromolecule
Name: POTASSIUM ION / type: ligand / ID: 6 / Number of copies: 4 / Formula: K
Molecular weight
Theoretical: 39.098 Da
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Experimental details
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Structure determination
Method
cryo EM
Processing
single particle reconstruction
Aggregation state
particle
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Sample preparation
Concentration
0.1 mg/mL
Buffer
pH: 7.5 Component:
Concentration
Name
25.0 mM
HEPES
75.0 mM
Potassium acetate
0.5 mM
TCEP
0.1 %
Glutaraldehyde
50.0 mM
Tris-HClTris
Grid
Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GRAPHENE OXIDE / Support film - topology: HOLEY ARRAY / Pretreatment - Type: GLOW DISCHARGE / Details: 40 mA for 120 sec
Vitrification
Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: Blot for 3 seconds, blot force 10.
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Electron microscopy
Microscope
FEI TITAN KRIOS
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Film or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 2 / Number real images: 3075 / Average exposure time: 60.0 sec. / Average electron dose: 34.0 e/Å2
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