Forkhead Box Protein 3: Difference between revisions

<StructureSection load='1dq8' size='500' side='right' caption='Structure of the Forkhead domain of FOXP3 bound to NFAT and IL2 Promoter Oligonucleotide ([[3qrf]])' scene='Forkhead_Box_Protein_3/Opening/8'>

[[Image:Picturefoxp34.png|280px|left]]&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;[[Forkhead Box Protein 3]] ('''FOXP3''') is a member of the [[Forkhead box protein|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.<ref>PMID:19464984</ref> FOXP3 upregulates a number of genes like Cd25 and Ctla4 and represses other genes like [[IL-2]] and Ptpn22.<ref>PMID: 17237761</ref> 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.<ref>PMID: 19767756</ref> 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.<ref>PMID:11137993</ref> 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.<ref>PMID:17220892</ref> 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''.<ref>PMID:12612578</ref>  

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The interaction of FOXP3 with NFAT1 and the FOXP3-NFAT1 target sequences found in IL-2 has been investigated extensively. The <scene name='Forkhead_Box_Protein_3/Foxp3_monomer/1'>Forkhead domain of FOXP3</scene> appears to form a <scene name='Forkhead_Box_Protein_3/Foxp3_dimer/1'>domain swapped dimer</scene> with a <scene name='Forkhead_Box_Protein_3/Nfat_dimer/2'>dimerized rel homology region (RHR) of NFAT1</scene> and two unique [[DNA]] <scene name='Forkhead_Box_Protein_3/Oligonucleotides/2'>oligonucleotides</scene>, each containing distinct FOXP sites.<ref name="Chen">PMID: 21458306</ref>

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The FOXP3 forkhead domain forms a relatively unique <scene name='Forkhead_Box_Protein_3/Foxp3_dimer_2/1'>domain swapped dimer</scene> that bridges two unique oligonucletodies. This dimer is stabilized by a network of <scene name='Forkhead_Box_Protein_3/Dimer_hydrophobic/2'>hydrophobic</scene> (Phe340, Leu345, Trp348, Trp366, and Met370) and <scene name='Forkhead_Box_Protein_3/Dimer_hydrophobic/3'>aromatic residues</scene>, (Tyr364, Trp366, Phe371, Phe 373, and Trp381) all of which are highly conserved across the FOX superfamily. Mutations to several of these residues such as <scene name='Forkhead_Box_Protein_3/Mutations/2'>F371C, F373A and R347H</scene> are known to occur in IPEX patients. Phe373 is <scene name='Forkhead_Box_Protein_3/Phenylalanine_373/2'>buried within the hydrophobic core</scene> of the dimer interface and the F373A mutation disrupts dimer formation. The F371C mutation does not appear to disrupt dimerization, probably because the aromatic ring of the phenylalanine residue is <scene name='Forkhead_Box_Protein_3/Phenylalanine_371/1'>angled away from the dimer interface</scene> and thus probably does not play a critical role in dimer formation, but rather might disrupt overall FOXP3 function. Dimerization is unique to FOXP3 among the FOX superfamily likely due to residues <scene name='Forkhead_Box_Protein_3/Dimerizing_residues/1'>Trp348 and Met370</scene>. When these residues are mutated to Gln and Thr respectively, to match those residues found in FOXP2, dimer formation is abolished.<ref name="Chen"/> Here is a morph estimating the <scene name='Forkhead_Box_Protein_3/Morph/2'>transition from monomer to domain-swapped dimer</scene>.

 

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Clues toward the biological 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.<ref name="Chen"/> These findings are consistent with clinical data, such as an infant bearing the F373A mutation developing autoimmune insulin-dependent diabetes within two weeks of life.<ref>PMID: 16741580</ref> It is clear however from microarray data that not all known FOXP3 targets are impacted by FOXP3 dimer-disrupting mutations, indicating FOXP3 might form varied complexes depending upon the target it binds.<ref name="Chen"/>