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

     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 DNA , 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. 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.^[7] Here is a morph estimating the **transition from monomer to domain-swapped dimer**. Clues toward the mechanism of action as to how mutation of dimer-stabilizing residues of FOXP3 causes IPEX can be garnered from microarray studies, which revealed a number of improperly regulated FOXP3 targets such as IL-2 and Ptpn22, and from in vitro suppression assays, which revealed that a number of dimer-destabilzing mutations eliminated the suppresive capacity of FOXP3⁺ cells.^[7]

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 FOXP3 unable to bind nearby FOXP3 binding sites, due to steric hindrance.^[7]

^[7]

Talk about alignment with FOXP2 and fix the morph.