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** disrupt dimer formation and are known to occur in IPEX patients. Here is a morph estimating the **transition from monomer to domain-swapped dimer**. Talk about alignment with FOXP2 and fix the morph.

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