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- EMDB-40736: FoxP3 tetramer on TTTG repeats -

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Basic information

Entry
Database: EMDB / ID: EMD-40736
TitleFoxP3 tetramer on TTTG repeats
Map data
Sample
  • Complex: FoxP3-DNA complex
    • Protein or peptide: Forkhead box protein P3
    • DNA: DNA 72-mer
    • DNA: DNA 72-mer
KeywordsFoxP3 / STRs / transcriptional factor / FKH / TRANSCRIPTION / TRANSCRIPTION-DNA complex
Function / homology
Function and homology information


T cell tolerance induction / positive regulation of peripheral T cell tolerance induction / CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment / tolerance induction / establishment of endothelial blood-brain barrier / positive regulation of CD4-positive, alpha-beta T cell differentiation / negative regulation of alpha-beta T cell proliferation / response to rapamycin / alpha-beta T cell proliferation / negative regulation of interleukin-4 production ...T cell tolerance induction / positive regulation of peripheral T cell tolerance induction / CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment / tolerance induction / establishment of endothelial blood-brain barrier / positive regulation of CD4-positive, alpha-beta T cell differentiation / negative regulation of alpha-beta T cell proliferation / response to rapamycin / alpha-beta T cell proliferation / negative regulation of interleukin-4 production / negative regulation of CREB transcription factor activity / RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) / CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation / negative regulation of chronic inflammatory response / transforming growth factor beta1 production / negative regulation of T cell cytokine production / negative regulation of interleukin-5 production / regulation of isotype switching to IgG isotypes / regulatory T cell differentiation / tolerance induction to self antigen / negative regulation of defense response to virus / negative regulation of lymphocyte proliferation / T cell mediated immunity / negative regulation of T-helper 17 cell differentiation / positive regulation of transforming growth factor beta1 production / T cell anergy / positive regulation of T cell anergy / lymphocyte proliferation / negative regulation of immune response / immature T cell proliferation in thymus / positive regulation of T cell tolerance induction / CD4-positive, alpha-beta T cell differentiation / CD4-positive, alpha-beta T cell proliferation / positive regulation of immature T cell proliferation in thymus / positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation / negative regulation of CD4-positive, alpha-beta T cell proliferation / negative regulation of isotype switching to IgE isotypes / isotype switching to IgE isotypes / negative regulation of interleukin-17 production / regulation of T cell anergy / regulation of immunoglobulin production / positive regulation of regulatory T cell differentiation / myeloid cell homeostasis / negative regulation of cytokine production / negative regulation of interleukin-2 production / histone acetyltransferase binding / negative regulation of interleukin-10 production / NFAT protein binding / positive regulation of interleukin-4 production / negative regulation of NF-kappaB transcription factor activity / negative regulation of interleukin-6 production / B cell homeostasis / negative regulation of type II interferon production / negative regulation of tumor necrosis factor production / negative regulation of T cell proliferation / T cell proliferation / T cell activation / negative regulation of DNA-binding transcription factor activity / response to virus / negative regulation of inflammatory response / histone deacetylase binding / transcription corepressor activity / T cell receptor signaling pathway / DNA-binding transcription activator activity, RNA polymerase II-specific / gene expression / sequence-specific DNA binding / response to lipopolysaccharide / transcription by RNA polymerase II / DNA-binding transcription factor activity, RNA polymerase II-specific / chromatin remodeling / inflammatory response / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of cell population proliferation / negative regulation of gene expression / negative regulation of DNA-templated transcription / DNA-templated transcription / positive regulation of gene expression / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding / nucleus / metal ion binding / cytosol / cytoplasm
Similarity search - Function
: / FOXP, coiled-coil domain / : / FOXP coiled-coil domain / Fork head domain / Forkhead domain / Fork head domain profile. / FORKHEAD / Fork head domain conserved site 2 / Fork head domain signature 2. ...: / FOXP, coiled-coil domain / : / FOXP coiled-coil domain / Fork head domain / Forkhead domain / Fork head domain profile. / FORKHEAD / Fork head domain conserved site 2 / Fork head domain signature 2. / Zinc finger C2H2 type domain signature. / Zinc finger C2H2-type / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
Forkhead box protein P3
Similarity search - Component
Biological speciesMus musculus (house mouse) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsLeng F / Hur S
Funding support United States, 1 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nature / Year: 2023
Title: FOXP3 recognizes microsatellites and bridges DNA through multimerization.
Authors: Wenxiang Zhang / Fangwei Leng / Xi Wang / Ricardo N Ramirez / Jinseok Park / Christophe Benoist / Sun Hur /
Abstract: FOXP3 is a transcription factor that is essential for the development of regulatory T cells, a branch of T cells that suppress excessive inflammation and autoimmunity. However, the molecular ...FOXP3 is a transcription factor that is essential for the development of regulatory T cells, a branch of T cells that suppress excessive inflammation and autoimmunity. However, the molecular mechanisms of FOXP3 remain unclear. Here we here show that FOXP3 uses the forkhead domain-a DNA-binding domain that is commonly thought to function as a monomer or dimer-to form a higher-order multimer after binding to TG repeat microsatellites. The cryo-electron microscopy structure of FOXP3 in a complex with TG repeats reveals a ladder-like architecture, whereby two double-stranded DNA molecules form the two 'side rails' bridged by five pairs of FOXP3 molecules, with each pair forming a 'rung'. Each FOXP3 subunit occupies TGTTTGT within the repeats in a manner that is indistinguishable from that of FOXP3 bound to the forkhead consensus motif (TGTTTAC). Mutations in the intra-rung interface impair TG repeat recognition, DNA bridging and the cellular functions of FOXP3, all without affecting binding to the forkhead consensus motif. FOXP3 can tolerate variable inter-rung spacings, explaining its broad specificity for TG-repeat-like sequences in vivo and in vitro. Both FOXP3 orthologues and paralogues show similar TG repeat recognition and DNA bridging. These findings therefore reveal a mode of DNA recognition that involves transcription factor homomultimerization and DNA bridging, and further implicates microsatellites in transcriptional regulation and diseases.
History
DepositionMay 5, 2023-
Header (metadata) releaseOct 18, 2023-
Map releaseOct 18, 2023-
UpdateDec 27, 2023-
Current statusDec 27, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40736.png

Downloads & links

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Map

FileDownload / File: emd_40736.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 400 pix.
= 337.6 Å		0.84 Å/pix.
x 400 pix.
= 337.6 Å		0.84 Å/pix.
x 400 pix.
= 337.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.844 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.55
Minimum - Maximum-1.8208714 - 3.546858
Average (Standard dev.)0.0011455261 (±0.0702057)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 337.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_40736_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_40736_half_map_2.map
Projections & Slices
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Sample components

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Entire : FoxP3-DNA complex

EntireName: FoxP3-DNA complex
Components
  • Complex: FoxP3-DNA complex
    • Protein or peptide: Forkhead box protein P3
    • DNA: DNA 72-mer
    • DNA: DNA 72-mer

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Supramolecule #1: FoxP3-DNA complex

SupramoleculeName: FoxP3-DNA complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Forkhead box protein P3

MacromoleculeName: Forkhead box protein P3 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 27.282246 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: GSYPLLANGV CKWPGCEKVF EEPEEFLKHC QADHLLDEKG KAQCLLQREV VQSLEQQLEL EKEKLGAMQA HLAGKMALAK APSVASMDK SSCCIVATST QGSVLPAWSA PREAPDGGLF AVRRHLWGSH GNSSFPEFFH NMDYFKYHNM RPPFTYATLI R WAILEAPE ...String:
GSYPLLANGV CKWPGCEKVF EEPEEFLKHC QADHLLDEKG KAQCLLQREV VQSLEQQLEL EKEKLGAMQA HLAGKMALAK APSVASMDK SSCCIVATST QGSVLPAWSA PREAPDGGLF AVRRHLWGSH GNSSFPEFFH NMDYFKYHNM RPPFTYATLI R WAILEAPE RQRTLNEIYH WFTRMFAYFR NHPATWKNAI RHNLSLHKCF VRVESEKGAV WTVDEFEFRK KRSQRPNK

UniProtKB: Forkhead box protein P3

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Macromolecule #2: DNA 72-mer

MacromoleculeName: DNA 72-mer / type: dna / ID: 2 / Number of copies: 2 / Classification: DNA
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 22.07349 KDa
SequenceString: (DC)(DA)(DA)(DA)(DC)(DA)(DA)(DA)(DC)(DA) (DA)(DA)(DC)(DA)(DA)(DA)(DC)(DA)(DA)(DA) (DC)(DA)(DA)(DA)(DC)(DA)(DA)(DA)(DC) (DA)(DA)(DA)(DC)(DA)(DA)(DA)(DC)(DA)(DA) (DA) (DC)(DA)(DA)(DA)(DC)(DA) ...String:
(DC)(DA)(DA)(DA)(DC)(DA)(DA)(DA)(DC)(DA) (DA)(DA)(DC)(DA)(DA)(DA)(DC)(DA)(DA)(DA) (DC)(DA)(DA)(DA)(DC)(DA)(DA)(DA)(DC) (DA)(DA)(DA)(DC)(DA)(DA)(DA)(DC)(DA)(DA) (DA) (DC)(DA)(DA)(DA)(DC)(DA)(DA)(DA) (DC)(DA)(DA)(DA)(DC)(DA)(DA)(DA)(DC)(DA) (DA)(DA) (DC)(DA)(DA)(DA)(DC)(DA)(DA) (DA)(DC)(DA)(DA)(DA)

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Macromolecule #3: DNA 72-mer

MacromoleculeName: DNA 72-mer / type: dna / ID: 3 / Number of copies: 2 / Classification: DNA
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 22.307139 KDa
SequenceString: (DT)(DT)(DT)(DG)(DT)(DT)(DT)(DG)(DT)(DT) (DT)(DG)(DT)(DT)(DT)(DG)(DT)(DT)(DT)(DG) (DT)(DT)(DT)(DG)(DT)(DT)(DT)(DG)(DT) (DT)(DT)(DG)(DT)(DT)(DT)(DG)(DT)(DT)(DT) (DG) (DT)(DT)(DT)(DG)(DT)(DT) ...String:
(DT)(DT)(DT)(DG)(DT)(DT)(DT)(DG)(DT)(DT) (DT)(DG)(DT)(DT)(DT)(DG)(DT)(DT)(DT)(DG) (DT)(DT)(DT)(DG)(DT)(DT)(DT)(DG)(DT) (DT)(DT)(DG)(DT)(DT)(DT)(DG)(DT)(DT)(DT) (DG) (DT)(DT)(DT)(DG)(DT)(DT)(DT)(DG) (DT)(DT)(DT)(DG)(DT)(DT)(DT)(DG)(DT)(DT) (DT)(DG) (DT)(DT)(DT)(DG)(DT)(DT)(DT) (DG)(DT)(DT)(DT)(DG)

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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

Concentration1 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.1 µm / Nominal defocus min: 0.7000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7tdx

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 317175
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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