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- EMDB-28816: Wild type P53 dimer structure from human cancer cells -

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Basic information

Entry
Database: EMDB / ID: EMD-28816
TitleWild type P53 dimer structure from human cancer cells
Map dataP53 dimer structure
Sample
  • Cell: P53 dimer isolated from U87-MG cells
    • Protein or peptide: Cellular tumor antigen p53
Keywordscancer / tumor suppressor / cell cycle / apoptosis / DNA repair / ANTITUMOR PROTEIN
Function / homology
Function and homology information


Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / signal transduction by p53 class mediator / negative regulation of G1 to G0 transition / 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 / Activation of NOXA and translocation to mitochondria / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity ...Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / signal transduction by p53 class mediator / negative regulation of G1 to G0 transition / 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 / Activation of NOXA and translocation to mitochondria / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity / negative regulation of helicase activity / regulation of cell cycle G2/M phase transition / intrinsic apoptotic signaling pathway in response to hypoxia / regulation of fibroblast apoptotic process / oxidative stress-induced premature senescence / oligodendrocyte apoptotic process / negative regulation of miRNA processing / positive regulation of thymocyte apoptotic process / glucose catabolic process to lactate via pyruvate / regulation of tissue remodeling / positive regulation of mitochondrial membrane permeability / negative regulation of mitophagy / positive regulation of programmed necrotic cell death / mRNA transcription / bone marrow development / circadian behavior / histone deacetylase regulator activity / germ cell nucleus / regulation of mitochondrial membrane permeability involved in apoptotic process / RUNX3 regulates CDKN1A transcription / regulation of DNA damage response, signal transduction by p53 class mediator / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / TP53 Regulates Transcription of Death Receptors and Ligands / Activation of PUMA and translocation to mitochondria / DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / negative regulation of glial cell proliferation / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / negative regulation of neuroblast proliferation / Regulation of TP53 Activity through Association with Co-factors / mitochondrial DNA repair / T cell lineage commitment / negative regulation of DNA replication / ER overload response / B cell lineage commitment / positive regulation of cardiac muscle cell apoptotic process / thymocyte apoptotic process / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / TP53 Regulates Transcription of Caspase Activators and Caspases / cardiac septum morphogenesis / positive regulation of execution phase of apoptosis / entrainment of circadian clock by photoperiod / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / Zygotic genome activation (ZGA) / necroptotic process / positive regulation of release of cytochrome c from mitochondria / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / rRNA transcription / mitophagy / SUMOylation of transcription factors / negative regulation of telomere maintenance via telomerase / intrinsic apoptotic signaling pathway by p53 class mediator / general transcription initiation factor binding / Transcriptional Regulation by VENTX / DNA damage response, signal transduction by p53 class mediator / response to X-ray / replicative senescence / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / neuroblast proliferation / cellular response to UV-C / : / hematopoietic stem cell differentiation / negative regulation of reactive oxygen species metabolic process / chromosome organization / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / T cell proliferation involved in immune response / glial cell proliferation / embryonic organ development / positive regulation of RNA polymerase II transcription preinitiation complex assembly / Pyroptosis / cis-regulatory region sequence-specific DNA binding / hematopoietic progenitor cell differentiation / cellular response to glucose starvation / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / cellular response to actinomycin D / somitogenesis / type II interferon-mediated signaling pathway / negative regulation of stem cell proliferation / core promoter sequence-specific DNA binding / positive regulation of intrinsic apoptotic signaling pathway / negative regulation of fibroblast proliferation / gastrulation / MDM2/MDM4 family protein binding / cardiac muscle cell apoptotic process / transcription initiation-coupled chromatin remodeling / 14-3-3 protein binding / mitotic G1 DNA damage checkpoint signaling / Regulation of TP53 Activity through Acetylation / response to salt stress
Similarity search - Function
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 ...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 / p53-like tetramerisation domain superfamily / p53/RUNT-type transcription factor, DNA-binding domain superfamily / p53-like transcription factor, DNA-binding
Similarity search - Domain/homology
Cellular tumor antigen p53
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.2 Å
AuthorsSolares M / Kelly DF
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA193578 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA227261 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA219700 United States
CitationJournal: Chembiochem / Year: 2022
Title: High-Resolution Imaging of Human Cancer Proteins Using Microprocessor Materials.
Authors: Maria J Solares / G M Jonaid / William Y Luqiu / Samantha Berry / Janki Khadela / Yanping Liang / Madison C Evans / Kevin J Pridham / William J Dearnaley / Zhi Sheng / Deborah F Kelly /
Abstract: Mutations in tumor suppressor genes, such as Tumor Protein 53 (TP53), are heavily implicated in aggressive cancers giving rise to gain- and loss-of-function phenotypes. While individual domains of ...Mutations in tumor suppressor genes, such as Tumor Protein 53 (TP53), are heavily implicated in aggressive cancers giving rise to gain- and loss-of-function phenotypes. While individual domains of the p53 protein have been studied extensively, structural information for full-length p53 remains incomplete. Functionalized microprocessor chips (microchips) with properties amenable to electron microscopy permitted us to visualize complete p53 assemblies for the first time. The new structures revealed p53 in an inactive dimeric state independent of DNA binding. Residues located at the protein-protein interface corresponded with modification sites in cancer-related hot spots. Changes in these regions may amplify the toxic effects of clinical mutations. Taken together, these results contribute advances in technology and imaging approaches to decode native protein models in different states of activation.
History
DepositionNov 8, 2022-
Header (metadata) releaseNov 23, 2022-
Map releaseNov 23, 2022-
UpdateMay 1, 2024-
Current statusMay 1, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28816.png

Downloads & links

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Map

FileDownload / File: emd_28816.map.gz / Format: CCP4 / Size: 2.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationP53 dimer structure
Voxel sizeX=Y=Z: 1.1 Å
Density
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-4.2792163 - 8.506843
Average (Standard dev.)0.000000000015819 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-48-45-39
Dimensions979180
Spacing919780
CellA: 100.1 Å / B: 106.700005 Å / C: 88.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map 1

Fileemd_28816_half_map_1.map
AnnotationHalf Map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map 2

Fileemd_28816_half_map_2.map
AnnotationHalf Map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : P53 dimer isolated from U87-MG cells

EntireName: P53 dimer isolated from U87-MG cells
Components
  • Cell: P53 dimer isolated from U87-MG cells
    • Protein or peptide: Cellular tumor antigen p53

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Supramolecule #1: P53 dimer isolated from U87-MG cells

SupramoleculeName: P53 dimer isolated from U87-MG cells / type: cell / ID: 1 / Parent: 0 / Macromolecule list: all / Details: Native protein, wild-type with no tags
Source (natural)Organism: Homo sapiens (human) / Organ: Brain / Tissue: Brain tumor

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Macromolecule #1: Cellular tumor antigen p53

MacromoleculeName: Cellular tumor antigen p53 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Organ: brain tumor / Tissue: brain
Molecular weightTheoretical: 43.711176 KDa
SequenceString: MEEPQSDPSV EPPLSQETFS DLWKLLPENN VLSPLPSQAM DDLMLSPDDI EQWFTEDPGP DEAPRMPEAA PPVAPAPAAP TPAAPAPAP SWPLSSSVPS QKTYQGSYGF RLGFLHSGTA KSVTCTYSPA LNKMFCQLAK TCPVQLWVDS TPPPGTRVRA M AIYKQSQH ...String:
MEEPQSDPSV EPPLSQETFS DLWKLLPENN VLSPLPSQAM DDLMLSPDDI EQWFTEDPGP DEAPRMPEAA PPVAPAPAAP TPAAPAPAP SWPLSSSVPS QKTYQGSYGF RLGFLHSGTA KSVTCTYSPA LNKMFCQLAK TCPVQLWVDS TPPPGTRVRA M AIYKQSQH MTEVVRRCPH HERCSDSDGL APPQHLIRVE GNLRVEYLDD RNTFRHSVVV PYEPPEVGSD CTTIHYNYMC NS SCMGGMN RRPILTIITL EDSSGNLLGR NSFEVRVCAC PGRDRRTEEE NLRKKGEPHH ELPPGSTKRA LPNNTSSSPQ PKK KPLDGE YFTLQIRGRE RFEMFRELNE ALELKDAQAG KEPGGSRAHS SHLKSKKGQS TSRHKKLMFK TEGPDSD

UniProtKB: Cellular tumor antigen p53

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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

Concentration0.2 mg/mL
BufferpH: 7.5
Details: 20 mM HEPES (pH 7.5), 140 mM NaCl, 2 mM MgCl2, 2 mM CaCl2, 5 mM imidazole
GridModel: Homemade / Material: SILICON NITRIDE
Details: Silicon nitride chips coated with Ni-NTA layers prior to sample application
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK III
Details: The microchip samples were loaded into a FEI Mark III Vitrobot and flash-frozen into liquid ethane..
DetailsSample was placed on Silicon nitride chips coated with Ni-NTA layers

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Electron microscopy

MicroscopeTFS TALOS F200C
Image recordingFilm or detector model: FEI CETA (4k x 4k) / Number grids imaged: 10 / Number real images: 300 / Average exposure time: 1.0 sec. / Average electron dose: 5.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 5.0 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 142000
Sample stageSpecimen holder model: GATAN 626 SINGLE TILT LIQUID NITROGEN CRYO TRANSFER HOLDER
Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Tecnai F20 / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 8000
Startup modelType of model: NONE
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C2 (2 fold cyclic) / Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 4.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 8000
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION
Final 3D classificationNumber classes: 1 / Avg.num./class: 8000 / Software - Name: RELION

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 50
Output model

PDB-8f2h:
Wild type P53 dimer structure from human cancer cells

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