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- PDB-6z2k: The structure of the tetrameric HDAC1/MIDEAS/DNTTIP1 MiDAC deacet... -

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Basic information

Entry
Database: PDB / ID: 6z2k
TitleThe structure of the tetrameric HDAC1/MIDEAS/DNTTIP1 MiDAC deacetylase complex
Components
  • Deoxynucleotidyltransferase terminal-interacting protein 1
  • Histone deacetylase 1
  • Mitotic deacetylase-associated SANT domain protein
KeywordsGENE REGULATION / HDAC1 MIDEAS ELMSAN1 DNTTIP1 TDIF1 histone deacetylase MiDAC
Function / homology
Function and homology information


Loss of MECP2 binding ability to 5mC-DNA / Krueppel-associated box domain binding / Repression of WNT target genes / MECP2 regulates transcription of neuronal ligands / protein lysine delactylase activity / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / histone decrotonylase activity / fungiform papilla formation / negative regulation of androgen receptor signaling pathway ...Loss of MECP2 binding ability to 5mC-DNA / Krueppel-associated box domain binding / Repression of WNT target genes / MECP2 regulates transcription of neuronal ligands / protein lysine delactylase activity / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / histone decrotonylase activity / fungiform papilla formation / negative regulation of androgen receptor signaling pathway / 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 / histone H3K14 deacetylase activity, hydrolytic mechanism / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / histone H4K12 deacetylase activity, hydrolytic mechanism / protein deacetylation / Regulation of MITF-M-dependent genes involved in apoptosis / histone deacetylase / regulation of stem cell differentiation / STAT3 nuclear events downstream of ALK signaling / histone H3K9 deacetylase activity, hydrolytic mechanism / 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 / histone deacetylase activity / positive regulation of intracellular estrogen receptor signaling pathway / DNA methylation-dependent constitutive heterochromatin formation / Notch-HLH transcription pathway / negative regulation of gene expression, epigenetic / Sin3-type complex / E-box binding / G1/S-Specific Transcription / eyelid development in camera-type eye / positive regulation of stem cell population maintenance / negative regulation of intrinsic apoptotic signaling pathway / oligodendrocyte differentiation / odontogenesis of dentin-containing tooth / RNA Polymerase I Transcription Initiation / histone deacetylase complex / positive regulation of oligodendrocyte differentiation / Regulation of MECP2 expression and activity / G0 and Early G1 / negative regulation by host of viral transcription / hair follicle placode formation / NF-kappaB binding / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / heterochromatin / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / core promoter sequence-specific DNA binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / RNA polymerase II core promoter sequence-specific DNA binding / nucleosome binding / Nuclear events stimulated by ALK signaling in cancer / MECP2 regulates neuronal receptors and channels / negative regulation of canonical NF-kappaB signal transduction / Regulation of TP53 Activity through Acetylation / cellular response to platelet-derived growth factor stimulus / transcription repressor complex / Transcriptional and post-translational regulation of MITF-M expression and activity / 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) / HDACs deacetylate histones / positive regulation of smooth muscle cell proliferation / Deactivation of the beta-catenin transactivating complex / promoter-specific chromatin binding / negative regulation of transforming growth factor beta receptor signaling pathway / Downregulation of SMAD2/3:SMAD4 transcriptional activity / circadian regulation of gene expression / Formation of the beta-catenin:TCF transactivating complex / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / negative regulation of canonical Wnt signaling pathway / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / NoRC negatively regulates rRNA expression / NOTCH1 Intracellular Domain Regulates Transcription / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / neuron differentiation / transcription corepressor activity / p53 binding / heterochromatin formation / chromatin organization / chromosome / Factors involved in megakaryocyte development and platelet production / DNA-binding transcription factor binding / transcription regulator complex / Estrogen-dependent gene expression
Similarity search - Function
Terminal deoxynucleotidyltransferase-interacting factor 1 / DNTTIP1, dimerisation domain / : / DNTTIP1 dimerisation domain / TdIF1, C-terminal / : / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 ...Terminal deoxynucleotidyltransferase-interacting factor 1 / DNTTIP1, dimerisation domain / : / DNTTIP1 dimerisation domain / TdIF1, C-terminal / : / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / Histone deacetylase / SANT domain profile. / SANT domain / : / 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 / : / Histone deacetylase 1 / Mitotic deacetylase-associated SANT domain protein / Deoxynucleotidyltransferase terminal-interacting protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.5 Å
AuthorsFairall, L. / Saleh, A. / Ragan, T.J. / Millard, C.J. / Savva, C.G. / Schwabe, J.W.R.
Funding support United Kingdom, 3items
OrganizationGrant numberCountry
Wellcome Trust100237/Z/12/Z United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/N002954/1 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_PC_171136 United Kingdom
Citation
Journal: Nat Commun / Year: 2020
Title: The MiDAC histone deacetylase complex is essential for embryonic development and has a unique multivalent structure.
Authors: Robert E Turnbull / Louise Fairall / Almutasem Saleh / Emma Kelsall / Kyle L Morris / T J Ragan / Christos G Savva / Aditya Chandru / Christopher J Millard / Olga V Makarova / Corinne J ...Authors: Robert E Turnbull / Louise Fairall / Almutasem Saleh / Emma Kelsall / Kyle L Morris / T J Ragan / Christos G Savva / Aditya Chandru / Christopher J Millard / Olga V Makarova / Corinne J Smith / Alan M Roseman / Andrew M Fry / Shaun M Cowley / John W R Schwabe /
Abstract: MiDAC is one of seven distinct, large multi-protein complexes that recruit class I histone deacetylases to the genome to regulate gene expression. Despite implications of involvement in cell cycle ...MiDAC is one of seven distinct, large multi-protein complexes that recruit class I histone deacetylases to the genome to regulate gene expression. Despite implications of involvement in cell cycle regulation and in several cancers, surprisingly little is known about the function or structure of MiDAC. Here we show that MiDAC is important for chromosome alignment during mitosis in cancer cell lines. Mice lacking the MiDAC proteins, DNTTIP1 or MIDEAS, die with identical phenotypes during late embryogenesis due to perturbations in gene expression that result in heart malformation and haematopoietic failure. This suggests that MiDAC has an essential and unique function that cannot be compensated by other HDAC complexes. Consistent with this, the cryoEM structure of MiDAC reveals a unique and distinctive mode of assembly. Four copies of HDAC1 are positioned at the periphery with outward-facing active sites suggesting that the complex may target multiple nucleosomes implying a processive deacetylase function.
#1: Journal: Nucleic Acids Res / Year: 2015
Title: Structural and functional characterization of a cell cycle associated HDAC1/2 complex reveals the structural basis for complex assembly and nucleosome targeting.
Authors: Toshimasa Itoh / Louise Fairall / Frederick W Muskett / Charles P Milano / Peter J Watson / Nadia Arnaudo / Almutasem Saleh / Christopher J Millard / Mohammed El-Mezgueldi / Fabrizio Martino ...Authors: Toshimasa Itoh / Louise Fairall / Frederick W Muskett / Charles P Milano / Peter J Watson / Nadia Arnaudo / Almutasem Saleh / Christopher J Millard / Mohammed El-Mezgueldi / Fabrizio Martino / John W R Schwabe /
Abstract: Recent proteomic studies have identified a novel histone deacetylase complex that is upregulated during mitosis and is associated with cyclin A. This complex is conserved from nematodes to man and ...Recent proteomic studies have identified a novel histone deacetylase complex that is upregulated during mitosis and is associated with cyclin A. This complex is conserved from nematodes to man and contains histone deacetylases 1 and 2, the MIDEAS corepressor protein and a protein called DNTTIP1 whose function was hitherto poorly understood. Here, we report the structures of two domains from DNTTIP1. The amino-terminal region forms a tight dimerization domain with a novel structural fold that interacts with and mediates assembly of the HDAC1:MIDEAS complex. The carboxy-terminal domain of DNTTIP1 has a structure related to the SKI/SNO/DAC domain, despite lacking obvious sequence homology. We show that this domain in DNTTIP1 mediates interaction with both DNA and nucleosomes. Thus, DNTTIP1 acts as a dimeric chromatin binding module in the HDAC1:MIDEAS corepressor complex.
History
DepositionMay 16, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 8, 2020Provider: repository / Type: Initial release
Revision 2.0Oct 7, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_validate_close_contact / struct_conn / struct_site
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.type_symbol / _chem_comp.id / _chem_comp.name / _chem_comp.pdbx_synonyms / _entity.pdbx_description / _pdbx_entity_nonpoly.comp_id / _pdbx_entity_nonpoly.name / _pdbx_nonpoly_scheme.mon_id / _pdbx_nonpoly_scheme.pdb_mon_id / _pdbx_validate_close_contact.auth_atom_id_2 / _pdbx_validate_close_contact.auth_comp_id_2 / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_site.details / _struct_site.pdbx_auth_comp_id
Revision 2.1May 22, 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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  • Deposited structure unit
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  • EMDB-11042
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Assembly

Deposited unit
C: Histone deacetylase 1
E: Histone deacetylase 1
K: Histone deacetylase 1
I: Histone deacetylase 1
A: Deoxynucleotidyltransferase terminal-interacting protein 1
B: Deoxynucleotidyltransferase terminal-interacting protein 1
G: Deoxynucleotidyltransferase terminal-interacting protein 1
H: Deoxynucleotidyltransferase terminal-interacting protein 1
F: Mitotic deacetylase-associated SANT domain protein
D: Mitotic deacetylase-associated SANT domain protein
L: Mitotic deacetylase-associated SANT domain protein
J: Mitotic deacetylase-associated SANT domain protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)360,63428
Polymers357,42012
Non-polymers3,21516
Water00
1


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

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Components

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Protein , 3 types, 12 molecules CEKIABGHFDLJ

#1: Protein
Histone deacetylase 1 / HD1


Mass: 55178.906 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HDAC1, RPD3L1 / Plasmid: pcDNA3 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: Q13547, histone deacetylase
#2: Protein
Deoxynucleotidyltransferase terminal-interacting protein 1 / Terminal deoxynucleotidyltransferase-interacting factor 1 / TdT-interacting factor 1


Mass: 14381.293 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DNTTIP1, C20orf167, TDIF1 / Plasmid: pcDNA3 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: Q9H147
#3: Protein
Mitotic deacetylase-associated SANT domain protein / ELM2 and SANT domain-containing protein 1


Mass: 19794.771 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MIDEAS, C14orf117, C14orf43, ELMSAN1 / Plasmid: pcDNA3 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: Q6PJG2

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Non-polymers , 3 types, 16 molecules

#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#5: Chemical
ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: K
#6: Chemical
ChemComp-IHP / INOSITOL HEXAKISPHOSPHATE / MYO-INOSITOL HEXAKISPHOSPHATE / INOSITOL 1,2,3,4,5,6-HEXAKISPHOSPHATE


Mass: 660.035 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H18O24P6

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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: Tetrameric complex of the MiDAC deacetylase complex containing HDAC1, the ELM2-SANT domain of MIDEAS and the dimerisation domain of DNTTIP1
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.357 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293F
Buffer solutionpH: 7.5
Buffer component
IDConc.NameBuffer-ID
112.5 mMHEPES1
225 mMpotassium acetate1
30.25 mMTCEP1
40.1 %glutaraldehdye1
550 mMTris/HCl1
SpecimenConc.: 0.45 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: 30 mA for 30 sec / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil, UltrAuFoil, R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K / Details: Blot time 3 sec, 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: 75000 X / Calibrated magnification: 129629 X / Nominal defocus max: 500 nm / Nominal defocus min: 500 nm / Calibrated defocus min: 500 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 100 K / Temperature (min): 100 K
Image recordingAverage exposure time: 60 sec. / Electron dose: 36 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k) / Num. of grids imaged: 2 / Num. of real images: 2752
EM imaging opticsPhase plate: VOLTA PHASE PLATE
Image scansSampling size: 14 µm / Width: 4096 / Height: 4096

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Processing

SoftwareName: PHENIX / Version: 1.14_3260: / Classification: refinement
EM software
IDNameVersionCategory
1RELION3particle selection
2EPU1.9image acquisition
4Gctf1.18CTF correction
7UCSF Chimera1.14model fitting
9PHENIX1.14model refinement
10RELION3initial Euler assignment
11RELION3final Euler assignment
12RELION3classification
13RELION33D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 151434
SymmetryPoint symmetry: D2 (2x2 fold dihedral)
3D reconstructionResolution: 4.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 63222 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT
Atomic model building

3D fitting-ID: 1 / Source name: PDB / Type: experimental model

IDPDB-IDPdb chain-IDAccession codeInitial refinement model-ID
15ICN

5icn

B5ICN1
24D6K

4d6k

4D6K2

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