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- PDB-8sro: FoxP3 tetramer on TTTG repeats -

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Basic information

Entry
Database: PDB / ID: 8sro
TitleFoxP3 tetramer on TTTG repeats
Components
  • (DNA 72-mer) x 2
  • Forkhead box protein P3
KeywordsTRANSCRIPTION/DNA / FoxP3 / 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 T cell cytokine production / transforming growth factor beta1 production / negative regulation of chronic inflammatory response / 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 / positive regulation of T cell tolerance induction / immature T cell proliferation in thymus / negative regulation of isotype switching to IgE isotypes / isotype switching to IgE isotypes / CD4-positive, alpha-beta T cell differentiation / positive regulation of immature T cell proliferation in thymus / CD4-positive, alpha-beta T cell proliferation / positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation / regulation of immunoglobulin production / negative regulation of immune response / negative regulation of CD4-positive, alpha-beta T cell proliferation / positive regulation of regulatory T cell differentiation / negative regulation of interleukin-17 production / regulation of T cell anergy / myeloid cell homeostasis / negative regulation of cytokine production / negative regulation of NF-kappaB transcription factor activity / negative regulation of interleukin-2 production / histone acetyltransferase binding / negative regulation of interleukin-10 production / NFAT protein binding / positive regulation of interleukin-4 production / B cell homeostasis / negative regulation of interleukin-6 production / 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 / response to virus / negative regulation of DNA-binding transcription factor activity / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / histone deacetylase binding / transcription corepressor activity / T cell receptor signaling pathway / gene expression / DNA-binding transcription activator activity, RNA polymerase II-specific / sequence-specific DNA binding / response to lipopolysaccharide / transcription by RNA polymerase II / DNA-binding transcription factor activity, RNA polymerase II-specific / inflammatory response / chromatin remodeling / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / 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
DNA / DNA (> 10) / Forkhead box protein P3
Similarity search - Component
Biological speciesMus musculus (house mouse)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsLeng, F. / Hur, S.
Funding support United States, 1items
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, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 18, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 13, 2023Group: 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 1.2Dec 27, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Forkhead box protein P3
D: Forkhead box protein P3
B: Forkhead box protein P3
C: Forkhead box protein P3
J: DNA 72-mer
I: DNA 72-mer
F: DNA 72-mer
E: DNA 72-mer


Theoretical massNumber of molelcules
Total (without water)197,8908
Polymers197,8908
Non-polymers00
Water00
1


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

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Components

#1: Protein
Forkhead box protein P3 / Scurfin


Mass: 27282.246 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Foxp3 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q99JB6
#2: DNA chain DNA 72-mer


Mass: 22073.490 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: DNA chain DNA 72-mer


Mass: 22307.139 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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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: FoxP3-DNA complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.5
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 defocus max: 2100 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 317175 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0034401
ELECTRON MICROSCOPYf_angle_d0.5296305
ELECTRON MICROSCOPYf_dihedral_angle_d28.2141089
ELECTRON MICROSCOPYf_chiral_restr0.032690
ELECTRON MICROSCOPYf_plane_restr0.003551

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