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protein dna_rna metals Protein-protein interface(s) links
Transcription/DNA PDB id
2as5
Jmol
Contents
Protein chains
287 a.a. *
83 a.a. *
DNA/RNA
Metals
_MG ×2
Waters ×115
* Residue conservation analysis
PDB id:
2as5
Name: Transcription/DNA
Title: Structure of the DNA binding domains of nfat and foxp2 bound specifically to DNA.
Structure: 5'- d(tp Tp Ap Gp Gp Ap Ap Ap Ap Tp Tp Tp Gp Tp Tp Tp Cp Ap Tp Ap Gp )-3'. Chain: a, c. Engineered: yes. 5'- d(ap Ap Cp Tp Ap Tp Gp Ap Ap Ap Cp Ap Ap Ap Tp Tp Tp Tp Cp Cp Tp )-3'. Chain: b, d.
Source: Synthetic: yes. Other_details: solid phase synthesis. Homo sapiens. Human. Organism_taxid: 9606. Gene: nfatc2, nfat1, nfatp. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Gene: foxp2.
Biol. unit: Octamer (from PQS)
Resolution:
2.70Å     R-factor:   0.238     R-free:   0.287
Authors: Y.Wu,J.C.Stroud,M.Borde,D.L.Bates,L.Guo,A.Han,A.Rao,L.Chen
Key ref:
Y.Wu et al. (2006). FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell, 126, 375-387. PubMed id: 16873067 DOI: 10.1016/j.cell.2006.05.042
Date:
22-Aug-05     Release date:   08-Aug-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q13469  (NFAC2_HUMAN) -  Nuclear factor of activated T-cells, cytoplasmic 2
Seq:
Struc: 		 
Seq:
Struc: 		925 a.a.
287 a.a.
Protein chains
Pfam   ArchSchema ?
O15409  (FOXP2_HUMAN) -  Forkhead box protein P2
Seq:
Struc: 		 
Seq:
Struc: 		715 a.a.
83 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     regulation of transcription   2 terms 
  Biochemical function     transcription factor activity     2 terms  

 

 
DOI no: 10.1016/j.cell.2006.05.042 Cell 126:375-387 (2006)
PubMed id: 16873067  
 
 
FOXP3 controls regulatory T cell function through cooperation with NFAT.
Y.Wu, M.Borde, V.Heissmeyer, M.Feuerer, A.D.Lapan, J.C.Stroud, D.L.Bates, L.Guo, A.Han, S.F.Ziegler, D.Mathis, C.Benoist, L.Chen, A.Rao.
 
  ABSTRACT  
 
Antigen stimulation of immune cells activates the transcription factor NFAT, a key regulator of T cell activation and anergy. NFAT forms cooperative complexes with the AP-1 family of transcription factors and regulates T cell activation-associated genes. Here we show that regulatory T cell (Treg) function is mediated by an analogous cooperative complex of NFAT with the forkhead transcription factor FOXP3, a lineage specification factor for Tregs. The crystal structure of an NFAT:FOXP2:DNA complex reveals an extensive protein-protein interaction interface between NFAT and FOXP2. Structure-guided mutations of FOXP3, predicted to progressively disrupt its interaction with NFAT, interfere in a graded manner with the ability of FOXP3 to repress expression of the cytokine IL2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function in a murine model of autoimmune diabetes. Thus by switching transcriptional partners, NFAT converts the acute T cell activation program into the suppressor program of Tregs.
 
  Selected figure(s)  
 
Figure 3.
Figure 3. Protein-Protein Interactions between NFAT and FOXP 		Figure 8.
Figure 8. T Regulatory Function Requires the NFAT:FOXP3 Interface
 
  The above figures are reprinted by permission from Cell Press: Cell (2006, 126, 375-387) copyright 2006.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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Structure of a domain-swapped FOXP3 dimer on DNA and its function in regulatory T cells.
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PDB code: 3qrf
21270769 I.Tsaur, M.Gasser, B.Aviles, J.Lutz, L.Lutz, M.Grimm, V.Lange, K.Lopau, U.Heemann, C.T.Germer, A.Chandraker, and A.M.Waaga-Gasser (2011).
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PDB code: 2kiu
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PDB code: 3g73
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Differentiation of effector CD4 T cell populations (*).
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Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors.
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Regulatory T cells exert checks and balances on self tolerance and autoimmunity.
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STIM proteins: integrators of signalling pathways in development, differentiation and disease.
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Regulatory T cells and breast cancer: implications for immunopathogenesis.
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20725108 M.R.Müller, and A.Rao (2010).
NFAT, immunity and cancer: a transcription factor comes of age.
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Synergistic and combinatorial control of T cell activation and differentiation by transcription factors.
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Clues to immune tolerance: the monogenic autoimmune syndromes.
  Ann N Y Acad Sci, 1214, 138-155.  
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NFAT pulls the strings during CD4+ T helper cell effector functions.
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20942809 N.Inoue, M.Watanabe, M.Morita, R.Tomizawa, T.Akamizu, K.Tatsumi, Y.Hidaka, and Y.Iwatani (2010).
Association of functional polymorphisms related to the transcriptional level of FOXP3 with prognosis of autoimmune thyroid diseases.
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Dual function of CTLA-4 in regulatory T cells and conventional T cells to prevent multiorgan autoimmunity.
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Intravenous apoptotic cell infusion as a cell-based therapy toward improving hematopoietic cell transplantation outcome.
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Hyperactivation of nuclear factor of activated T cells 1 (NFAT1) in T cells attenuates severity of murine autoimmune encephalomyelitis.
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A CD8 T cell-intrinsic role for the calcineurin-NFAT pathway for tolerance induction in vivo.
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TGF-beta and 'adaptive' Foxp3(+) regulatory T cells.
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FOXP3 expression and clinical characteristics of hepatocellular carcinoma.
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Crystal structure of the p53 core domain bound to a full consensus site as a self-assembled tetramer.
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PDB code: 3kmd
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