Forkhead Box Protein 3

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   Print3D      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. FOXP3 upregulates a number of genes like Cd25 and Ctla4 and represses other genes like IL-2 and Ptpn22. 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. 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. 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. 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.      The interaction of FOXP3 with NFAT1 and the FOXP3-NFAT1 target sequences found in IL-2 has been investigated extensively. The Forkhead domain of FOXP3 appears to form a domain swapped dimer with a dimerized rel homology region (RHR) of NFAT1 and two unique oligonucleotides, each containing distinct FOXP sites. 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. The FOXP3 Forkhead Domain forms a relatively unique **domain swapped dimer** that bridges two unique oligonucletodies. This dimer is stabilized by a network of **hydrophobic** (Phe340, Leu345, Trp348, Trp366, and Met370)and **aromatic residues,** (Tyr364, Trp366, Phe371, Phe 373, and Trp381) all of which are highly conserved across the FOX superfamily. Mutations to several of these residues, and others, such as **F371C, F373A, R347A** interfere with dimer formation and are known to occur in IPEX patients. Dimerization is unique to FOXP3 among the FOX superfamily likely due to residues **Trp348 and Met370**. When these residues are mutated to Gln and Thr respectively, to match those residues found in FOXP2, dimer formation is abolished. Here is a morph estimating the **transition from monomer to domain-swapped dimer**. The two DNA binding helices bind unique sequences from the IL-2 promoter, primarily utilizing residues **asfdasdfsafdasf**. These oligonucletodies are held in an antiparllel conformation, making it unlikely that FOXP3 would be able to bind nearby FOXP3 binding sites, due to steric hindrance. Talk about alignment with FOXP2 and fix the morph.

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