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- PDB-7ao8: Structure of the MTA1/HDAC1/MBD2 NURD deacetylase complex -

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Basic information

Entry
Database: PDB / ID: 7ao8
TitleStructure of the MTA1/HDAC1/MBD2 NURD deacetylase complex
Components
  • Histone deacetylase 1
  • Metastasis-associated protein MTA1
  • Methyl-CpG-binding domain protein 2
KeywordsTRANSCRIPTION / Deacetylase / Complex
Function / homology
Function and homology information


Loss of MECP2 binding ability to 5mC-DNA / Krueppel-associated box domain binding / Repression of WNT target genes / satellite DNA binding / MECP2 regulates transcription of neuronal ligands / protein lysine delactylase activity / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / histone decrotonylase activity / ventricular cardiac muscle tissue development ...Loss of MECP2 binding ability to 5mC-DNA / Krueppel-associated box domain binding / Repression of WNT target genes / satellite DNA binding / MECP2 regulates transcription of neuronal ligands / protein lysine delactylase activity / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / histone decrotonylase activity / ventricular cardiac muscle tissue development / negative regulation of androgen receptor signaling pathway / fungiform papilla formation / positive regulation of signaling receptor activity / NuRD complex / regulation of cell fate specification / endoderm development / negative regulation of stem cell population maintenance / histone H4K16 deacetylase activity, hydrolytic mechanism / histone H4K5 deacetylase activity, hydrolytic mechanism / histone H4K8 deacetylase activity, hydrolytic mechanism / histone H3K4 deacetylase activity, hydrolytic mechanism / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / histone H3K14 deacetylase activity, hydrolytic mechanism / siRNA binding / protein deacetylation / histone H4K12 deacetylase activity, hydrolytic mechanism / Regulation of MITF-M-dependent genes involved in apoptosis / maternal behavior / regulation of stem cell differentiation / STAT3 nuclear events downstream of ALK signaling / histone deacetylase / C2H2 zinc finger domain binding / histone H3K9 deacetylase activity, hydrolytic mechanism / positive regulation of protein autoubiquitination / tubulin deacetylase activity / methyl-CpG binding / Transcription of E2F targets under negative control by DREAM complex / protein lysine deacetylase activity / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / embryonic digit morphogenesis / response to ionizing radiation / histone deacetylase activity / DNA methylation-dependent constitutive heterochromatin formation / negative regulation of gene expression, epigenetic / Notch-HLH transcription pathway / entrainment of circadian clock by photoperiod / positive regulation of stem cell population maintenance / eyelid development in camera-type eye / G1/S-Specific Transcription / Sin3-type complex / E-box binding / negative regulation of intrinsic apoptotic signaling pathway / oligodendrocyte differentiation / locomotor rhythm / odontogenesis of dentin-containing tooth / SUMOylation of transcription factors / RNA Polymerase I Transcription Initiation / histone deacetylase complex / Regulation of MECP2 expression and activity / positive regulation of oligodendrocyte differentiation / hair follicle placode formation / G0 and Early G1 / : / positive regulation of Wnt signaling pathway / negative regulation by host of viral transcription / NF-kappaB binding / embryonic organ development / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / Transcriptional and post-translational regulation of MITF-M expression and activity / heterochromatin / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / RNA polymerase II core promoter sequence-specific DNA binding / core promoter sequence-specific DNA binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / response to mechanical stimulus / Nuclear events stimulated by ALK signaling in cancer / negative regulation of canonical NF-kappaB signal transduction / MECP2 regulates neuronal receptors and channels / Regulation of TP53 Activity through Acetylation / cellular response to platelet-derived growth factor stimulus / transcription repressor complex / RNA Polymerase I Promoter Opening / SUMOylation of chromatin organization proteins / negative regulation of cell migration / hippocampus development / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / Regulation of PTEN gene transcription / transcription corepressor binding / Regulation of endogenous retroelements by KRAB-ZFP proteins / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / promoter-specific chromatin binding / Deactivation of the beta-catenin transactivating complex / HDACs deacetylate histones / positive regulation of smooth muscle cell proliferation / Downregulation of SMAD2/3:SMAD4 transcriptional activity / circadian regulation of gene expression / negative regulation of transforming growth factor beta receptor signaling pathway / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Formation of the beta-catenin:TCF transactivating complex / negative regulation of canonical Wnt signaling pathway
Similarity search - Function
Metastasis-associated protein MTA1, R1 domain / Mesoderm induction early response protein/metastasis-associated protein / MTA R1 domain / Methyl-CpG binding protein 2/3, C-terminal domain / Methyl-CpG-binding domain protein 2/3, p55-binding region / C-terminal domain of methyl-CpG binding protein 2 and 3 / p55-binding region of Methyl-CpG-binding domain proteins MBD / zinc finger binding to DNA consensus sequence [AT]GATA[AG] / GATA zinc finger / Zinc finger, GATA-type ...Metastasis-associated protein MTA1, R1 domain / Mesoderm induction early response protein/metastasis-associated protein / MTA R1 domain / Methyl-CpG binding protein 2/3, C-terminal domain / Methyl-CpG-binding domain protein 2/3, p55-binding region / C-terminal domain of methyl-CpG binding protein 2 and 3 / p55-binding region of Methyl-CpG-binding domain proteins MBD / zinc finger binding to DNA consensus sequence [AT]GATA[AG] / GATA zinc finger / Zinc finger, GATA-type / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / Histone deacetylase / Bromo adjacent homology domain / BAH domain / Bromo adjacent homology (BAH) domain / Bromo adjacent homology (BAH) domain superfamily / BAH domain profile. / SANT domain profile. / SANT domain / Myb-like DNA-binding domain / Methyl-CpG binding domain / Methyl-CpG DNA binding / Methyl-CpG binding domain / Methyl-CpG-binding domain (MBD) profile. / : / DNA-binding domain superfamily / Histone deacetylase family / Histone deacetylase domain / Histone deacetylase domain superfamily / Histone deacetylase domain / Ureohydrolase domain superfamily / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / Homeobox-like domain superfamily
Similarity search - Domain/homology
INOSITOL HEXAKISPHOSPHATE / : / Metastasis-associated protein MTA1 / Histone deacetylase 1 / Methyl-CpG-binding domain protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.5 Å
AuthorsMillard, C.J. / Fairall, L. / Ragan, T.J. / Savva, C.G. / Schwabe, J.W.R.
Funding support United Kingdom, 3items
OrganizationGrant numberCountry
Wellcome TrustWT100237/Z/12/Z United Kingdom
Medical Research Council (MRC, United Kingdom)MC_PC_17136 United Kingdom
Wolfson Foundation United Kingdom
CitationJournal: 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
DepositionOct 14, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 11, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 30, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2May 1, 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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Structure viewerMolecule:
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Assembly

Deposited unit
C: Methyl-CpG-binding domain protein 2
D: Metastasis-associated protein MTA1
A: Metastasis-associated protein MTA1
E: Histone deacetylase 1
B: Histone deacetylase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)317,09713
Polymers315,4905
Non-polymers1,6078
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, A flag tag on MTA1 was used to purify the complex.
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area17000 Å2
ΔGint-149 kcal/mol
Surface area59600 Å2
MethodPISA

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Components

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Protein , 3 types, 5 molecules CDAEB

#1: Protein Methyl-CpG-binding domain protein 2 / Demethylase / DMTase / Methyl-CpG-binding protein MBD2


Mass: 43323.625 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MBD2 / Production host: Homo sapiens (human) / References: UniProt: Q9UBB5
#2: Protein Metastasis-associated protein MTA1


Mass: 80904.312 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MTA1 / Cell (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q13330
#3: Protein Histone deacetylase 1 / HD1


Mass: 55178.906 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HDAC1, RPD3L1 / Cell (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q13547, histone deacetylase

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Non-polymers , 3 types, 8 molecules

#4: Chemical ChemComp-IHP / INOSITOL HEXAKISPHOSPHATE / MYO-INOSITOL HEXAKISPHOSPHATE / INOSITOL 1,2,3,4,5,6-HEXAKISPHOSPHATE


Mass: 660.035 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H18O24P6
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#6: Chemical
ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: K

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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: NuRD deacetylase complex containing two copies of MTA1 and HDAC1 and a single copy of MBD2
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.22 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameBuffer-ID
125 mMHEPES1
275 mMPotassium acetate1
30.5 mMTCEP1
40.1 %Glutaraldehyde1
550 mMTris-HCl1
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: 40 mA for 120 sec / 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 / Details: Blot for 3 seconds, blot force 10

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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: 81000 X / Nominal defocus min: 500 nm / Calibrated defocus min: 500 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (min): 100 K
Image recordingAverage exposure time: 5 sec. / Electron dose: 42 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 15086
Image scansWidth: 5760 / Height: 4092

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Processing

EM software
IDNameVersionCategory
1RELION3particle selection
2EPU1.9image acquisition
4Gctf1.18CTF correction
7UCSF Chimera1.13.1model fitting
10RELION3initial Euler assignment
11RELION3final Euler assignment
12RELION3classification
13RELION33D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 324135
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 94041 / Num. of class averages: 3 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
15ICN

5icn

15ICN1PDBexperimental model
22KY8

2ky8

12KY82PDBexperimental model

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