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- PDB-5xzc: Cryo-EM structure of p300-p53 protein complex -

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Basic information

Entry
Database: PDB / ID: 5xzc
TitleCryo-EM structure of p300-p53 protein complex
Components
  • Cellular tumor antigen p53
  • Histone acetyltransferase p300
KeywordsTRANSCRIPTION / transcription factor / autoacetylation / allosteric interaction / catalytically active form
Function / homology
Function and homology information


behavioral defense response / negative regulation of protein oligomerization / peptidyl-lysine propionylation / histone lactyltransferase (CoA-dependent) activity / peptidyl-lysine crotonylation / peptidyl-lysine butyrylation / histone butyryltransferase activity / swimming / histone H3K122 acetyltransferase activity / peptide butyryltransferase activity ...behavioral defense response / negative regulation of protein oligomerization / peptidyl-lysine propionylation / histone lactyltransferase (CoA-dependent) activity / peptidyl-lysine crotonylation / peptidyl-lysine butyrylation / histone butyryltransferase activity / swimming / histone H3K122 acetyltransferase activity / peptide butyryltransferase activity / regulation of tubulin deacetylation / histone H2B acetyltransferase activity / internal protein amino acid acetylation / peptide 2-hydroxyisobutyryltransferase activity / histone crotonyltransferase activity / protein propionyltransferase activity / NOTCH2 intracellular domain regulates transcription / thigmotaxis / L-lysine N-acetyltransferase activity, acting on acetyl phosphate as donor / positive regulation of TORC2 signaling / internal peptidyl-lysine acetylation / histone H4 acetyltransferase activity / cellular response to L-leucine / histone H3 acetyltransferase activity / NFE2L2 regulating ER-stress associated genes / acetylation-dependent protein binding / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / NGF-stimulated transcription / histone H3K18 acetyltransferase activity / N-terminal peptidyl-lysine acetylation / histone H3K27 acetyltransferase activity / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / NFE2L2 regulates pentose phosphate pathway genes / STAT3 nuclear events downstream of ALK signaling / NFE2L2 regulating MDR associated enzymes / Polo-like kinase mediated events / negative regulation of helicase activity / Loss of function of TP53 in cancer due to loss of tetramerization ability / host-mediated activation of viral transcription / Regulation of TP53 Expression / signal transduction by p53 class mediator / negative regulation of G1 to G0 transition / TGFBR3 expression / negative regulation of glucose catabolic process to lactate via pyruvate / Transcriptional activation of cell cycle inhibitor p21 / regulation of intrinsic apoptotic signaling pathway by p53 class mediator / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity / Activation of NOXA and translocation to mitochondria / regulation of androgen receptor signaling pathway / regulation of cell cycle G2/M phase transition / oligodendrocyte apoptotic process / negative regulation of miRNA processing / intrinsic apoptotic signaling pathway in response to hypoxia / regulation of fibroblast apoptotic process / positive regulation of thymocyte apoptotic process / oxidative stress-induced premature senescence / regulation of mitochondrion organization / regulation of tissue remodeling / positive regulation of mitochondrial membrane permeability / mRNA transcription / bone marrow development / Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells / positive regulation of programmed necrotic cell death / Regulation of FOXO transcriptional activity by acetylation / RUNX3 regulates NOTCH signaling / circadian behavior / T cell proliferation involved in immune response / regulation of mitochondrial membrane permeability involved in apoptotic process / germ cell nucleus / NOTCH4 Intracellular Domain Regulates Transcription / RUNX3 regulates CDKN1A transcription / Nuclear events mediated by NFE2L2 / Regulation of NFE2L2 gene expression / face morphogenesis / glucose catabolic process to lactate via pyruvate / Regulation of gene expression by Hypoxia-inducible Factor / TP53 Regulates Transcription of Death Receptors and Ligands / Activation of PUMA and translocation to mitochondria / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / platelet formation / regulation of DNA damage response, signal transduction by p53 class mediator / NOTCH3 Intracellular Domain Regulates Transcription / regulation of glycolytic process / histone deacetylase regulator activity / TRAF6 mediated IRF7 activation / NFE2L2 regulating tumorigenic genes / negative regulation of glial cell proliferation / Regulation of TP53 Activity through Association with Co-factors / NFE2L2 regulating anti-oxidant/detoxification enzymes / megakaryocyte development / negative regulation of neuroblast proliferation / protein-lysine-acetyltransferase activity / acyltransferase activity / mitochondrial DNA repair / nuclear androgen receptor binding / T cell lineage commitment / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / protein acetylation
Similarity search - Function
Nuclear receptor coactivator, CREB-bp-like, interlocking / Nuclear receptor coactivator, CREB-bp-like, interlocking domain superfamily / Creb binding / Zinc finger, TAZ-type / TAZ domain superfamily / TAZ zinc finger / Zinc finger TAZ-type profile. / TAZ zinc finger, present in p300 and CBP / : / Histone acetyltransferase p300-like, PHD domain ...Nuclear receptor coactivator, CREB-bp-like, interlocking / Nuclear receptor coactivator, CREB-bp-like, interlocking domain superfamily / Creb binding / Zinc finger, TAZ-type / TAZ domain superfamily / TAZ zinc finger / Zinc finger TAZ-type profile. / TAZ zinc finger, present in p300 and CBP / : / Histone acetyltransferase p300-like, PHD domain / Coactivator CBP, KIX domain / CREB-binding protein/p300, atypical RING domain / CBP/p300-type histone acetyltransferase domain / CBP/p300, atypical RING domain superfamily / KIX domain / CREB-binding protein/p300, atypical RING domain / KIX domain profile. / CBP/p300-type histone acetyltransferase (HAT) domain profile. / Histone acetyltransferase Rtt109/CBP / Histone acetylation protein / Histone acetylation protein / Coactivator CBP, KIX domain superfamily / Cellular tumor antigen p53, transactivation domain 2 / Transactivation domain 2 / p53 transactivation domain / P53 transactivation motif / p53 family signature. / p53, tetramerisation domain / P53 tetramerisation motif / p53, DNA-binding domain / P53 DNA-binding domain / p53 tumour suppressor family / Zinc finger ZZ-type signature. / p53-like tetramerisation domain superfamily / p53/RUNT-type transcription factor, DNA-binding domain superfamily / Zinc-binding domain, present in Dystrophin, CREB-binding protein. / Zinc finger, ZZ type / Zinc finger, ZZ-type / Zinc finger, ZZ-type superfamily / Zinc finger ZZ-type profile. / p53-like transcription factor, DNA-binding / Nuclear receptor coactivator, interlocking / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
Cellular tumor antigen p53 / Histone acetyltransferase p300
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 10.7 Å
AuthorsGhosh, R. / Roy, S. / Sengupta, J.
CitationJournal: Biochemistry / Year: 2019
Title: Tumor Suppressor p53-Mediated Structural Reorganization of the Transcriptional Coactivator p300.
Authors: Raka Ghosh / Stephanie Kaypee / Manidip Shasmal / Tapas K Kundu / Siddhartha Roy / Jayati Sengupta /
Abstract: Transcriptional coactivator p300, a critical player in eukaryotic gene regulation, primarily functions as a histone acetyltransferase (HAT). It is also an important player in acetylation of a number ...Transcriptional coactivator p300, a critical player in eukaryotic gene regulation, primarily functions as a histone acetyltransferase (HAT). It is also an important player in acetylation of a number of nonhistone proteins, p53 being the most prominent one. Recruitment of p300 to p53 is pivotal in the regulation of p53-dependent genes. Emerging evidence suggests that p300 adopts an active conformation upon binding to the tetrameric p53, resulting in its enhanced acetylation activity. As a modular protein, p300 consists of multiple well-defined domains, where the structured domains are interlinked with unstructured linker regions. A crystal structure of the central domain of p300 encompassing Bromo, RING, PHD, and HAT domains demonstrates a compact module, where the HAT active site stays occluded by the RING domain. However, although p300 has a significant role in mediating the transcriptional activity of p53, only a few structural details on the complex of these two full-length proteins are available. Here, we present a cryo-electron microscopy (cryo-EM) study on the p300-p53 complex. The three-dimensional cryo-EM density map of the p300-p53 complex, when compared to the cryo-EM map of free p300, revealed that substantial change in the relative arrangement of Bromo and HAT domains occurs upon complex formation, which is likely required for exposing HAT active site and subsequent acetyltransferase activity. Our observation correlates well with previous studies showing that the presence of Bromodomain is obligatory for effective acetyltransferase activity of HAT. Thus, our result sheds new light on the mechanism whereby p300, following binding with p53, gets activated.
History
DepositionJul 12, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 23, 2019Provider: repository / Type: Initial release
Revision 1.1Jul 31, 2019Group: Data collection / 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 27, 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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Assembly

Deposited unit
A: Histone acetyltransferase p300
B: Cellular tumor antigen p53
C: Cellular tumor antigen p53
D: Cellular tumor antigen p53
E: Cellular tumor antigen p53


Theoretical massNumber of molelcules
Total (without water)191,6965
Polymers191,6965
Non-polymers00
Water00
1
A: Histone acetyltransferase p300


Theoretical massNumber of molelcules
Total (without water)72,1001
Polymers72,1001
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_5551
2
B: Cellular tumor antigen p53
C: Cellular tumor antigen p53
D: Cellular tumor antigen p53
E: Cellular tumor antigen p53


Theoretical massNumber of molelcules
Total (without water)119,5964
Polymers119,5964
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_5551
DetailsOne molecule of p300 interacts with four molecules of p53 (i.e, p300 monomer interacts with p53 tetramer)

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Components

#1: Protein Histone acetyltransferase p300 / p300 HAT / E1A-associated protein p300 / Coordinate model: Cα atoms only


Mass: 72100.062 Da / Num. of mol.: 1 / Fragment: UNP residues 1046-1664
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EP300, P300 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q09472, histone acetyltransferase
#2: Protein
Cellular tumor antigen p53 / Antigen NY-CO-13 / Phosphoprotein p53 / Tumor suppressor p53 / Coordinate model: Cα atoms only


Mass: 29898.908 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TP53, P53 / Production host: Escherichia coli (E. coli) / References: UniProt: P04637

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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: p300-p53 complex / Type: COMPLEX
Details: Proteins were purified separately and then complex was made for cryo-EM.
Entity ID: all / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
110 mMTris-Cl1
2150 mMNacl1
35 mMMgCl21
420 microMZnCl21
52 mMPMSF1
61 mMDTT1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 279 K

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Electron microscopy imaging

Experimental equipment
Model: Tecnai Polara / Image courtesy: FEI Company
MicroscopyModel: FEI POLARA 300
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 59000 X / Calibrated magnification: 78894 X / Nominal defocus max: 4500 nm / Nominal defocus min: 1700 nm / Calibrated defocus min: 1700 nm / Calibrated defocus max: 4500 nm / Cs: 2 mm / C2 aperture diameter: 150 µm
Specimen holderCryogen: NITROGEN
Specimen holder model: GATAN 910 MULTI-SPECIMEN SINGLE TILT CRYO TRANSFER HOLDER
Image recordingAverage exposure time: 1 sec. / Electron dose: 15 e/Å2 / Film or detector model: FEI EAGLE (4k x 4k)

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Processing

EM software
IDNameVersionCategoryDetailsFitting-ID
1EMAN22.12particle selectionparticles picked semiautomatically: using both e2boxer.py and manually.
2SPIDERparticle selectionparticles picked in EMAN2 and exported to SPIDER and also particles were picked separately in SPIDER
3TIA4.7image acquisition
5EMAN22.12CTF correction
6SPIDERCTF correction
9UCSF Chimera1.11model fittingCrystal structure 4BHW fitted using Chimera. The bromodomain matches remarkably well with the central spout. RING and PHD domains are fitted manually at the weak densities beside the bromodomain.1
12PyMOLmodel fittingp53 dimers (pdb: 3KMD) fitted manually in both the side-lobes of p53 density.2
14EMAN22.12initial Euler assignment
15SPIDERfinal Euler assignment
16SPIDERclassification
17SPIDER3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 10.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 10088 / Algorithm: BACK PROJECTION / Symmetry type: POINT
Atomic model building
ID
1
2
Atomic model building

Source name: PDB / Type: experimental model

IDPDB-IDPdb chain-ID 3D fitting-IDAccession codeInitial refinement model-IDPdb chain residue range
14BHW

4bhw

A14BHW11046-1664
23KMD

3kmd

23KMD292-291
31C26

1c26

21C263325-356
RefinementHighest resolution: 10.7 Å

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