Forkhead Box Protein 3

From Proteopedia

Revision as of 21:34, 28 April 2012

spinqualitylabelsall models Structure of the Forkhead domain of FOXP3 bound to NFAT and IL2 Promoter Oligonucleotide (3qrf) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image      Forkhead Box Protein 3 (FOXP3) is a member of the Forkhead transcription factor family. It is highly expressed in regulatory T (Treg) cells, a subset of CD4+ T cells that play a critical role in suppressing immune responses, especially those mediated by autoreactive T cells.[1] FOXP3 upregulates a number of genes like Cd25 and Ctla4 and represses other genes like IL-2 and Ptpn22.[2] As with many transcription factors, it cooperates with a number of transcription factor partners to regulate gene expression, including NFAT1, which participates in the inducible expression of cytokine genes like IL-2, IL-4, and TNFα in T cells.[3] A number of mutations to FOXP3 are known to result in a severe autoimmune disease known as IPEX (immune dysregulation, polyendocriopthy, enteropathy, X-linked). As FOXP3 is found on the X-chromosome, mutations to FOXP3 typically only display deleterious phenotypic traits in males, resulting in lymphocyte infiltration and wide spread inflammation in inphants.[4] A similar pathology is also found in mice who carry nonsense mutations in the FOXP3 locus. These mutant mice are known as scurfy mice. The targeted elimination of FOXP3+ CD4+ Tregs in adult mice has similar autoimmune dysfunction.[5] Further, ectopic expression of FOXP3 in peripheral CD4+CD25- T cells equips these T cells with the ability to suppress the proliferation and effector functions of autoreactive T cells in vivo.[6]      The interaction of FOXP3 with NFAT1 and the FOXP3-NFAT1 target sequences found in IL-2 has been investigated extensively. The appears to form a with a and two unique , each containing distinct FOXP sites.[7] Each domain-swapped dimer of FOXP3 makes extensive interactions with NFAT1 involving FOXP3 **hydrogen bonding residues** Thr359, Asn361, His365, while Glu399 and Glu401 of FOXP3 **interact with a string of basic residues** including Lys664, Arg665, Lys666, and Arg667., among others, which were critical in the FOXP2-NFAT1 interaction. These interactions allow FOXP3 and NFAT1 to bind more tightly together than other NFAT1 complexes formed with other Forkhead box proteins.[7] The FOXP3 Forkhead Domain forms a relatively unique **domain swapped dimer** that bridges two unique oligonucletodies. Here is a morph estimating the **transition from monomer to domain-swapped dimer**. [7] Talk about alignment with FOXP2 and fix the morph.

References

1. ↑ Josefowicz SZ, Rudensky A. Control of regulatory T cell lineage commitment and maintenance. Immunity. 2009 May;30(5):616-25. PMID:19464984 doi:10.1016/j.immuni.2009.04.009
2. ↑ Zheng Y, Josefowicz SZ, Kas A, Chu TT, Gavin MA, Rudensky AY. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature. 2007 Feb 22;445(7130):936-40. Epub 2007 Jan 21. PMID:17237761 doi:10.1038/nature05563
3. ↑ Rudra D, Egawa T, Chong MM, Treuting P, Littman DR, Rudensky AY. Runx-CBFbeta complexes control expression of the transcription factor Foxp3 in regulatory T cells. Nat Immunol. 2009 Nov;10(11):1170-7. Epub 2009 Sep 20. PMID:19767756 doi:10.1038/ni.1795
4. ↑ Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001 Jan;27(1):20-1. PMID:11137993 doi:10.1038/83713
5. ↑ Williams LM, Rudensky AY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol. 2007 Mar;8(3):277-84. Epub 2007 Jan 14. PMID:17220892 doi:10.1038/ni1437
6. ↑ Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003 Apr;4(4):330-6. Epub 2003 Mar 3. PMID:12612578 doi:10.1038/ni904
7. ↑ ^{7.0 7.1 7.2} Bandukwala HS, Wu Y, Feurer M, Chen Y, Barbosa B, Ghosh S, Stroud JC, Benoist C, Mathis D, Rao A, Chen L. Structure of a Domain-Swapped FOXP3 Dimer on DNA and Its Function in Regulatory T Cells. Immunity. 2011 Mar 30. PMID:21458306 doi:10.1016/j.immuni.2011.02.017