Forkhead Box Protein 3: Difference between revisions

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Alexander Berchansky, David Canner

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 &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;Each domain-swapped dimer of FOXP3 makes extensive interactions with NFAT1 involving FOXP3 <scene name='Forkhead_Box_Protein_3/H_bonding_to_nfat/1'>hydrogen bonding residues</scene> Thr359, Asn361, His365, while Glu399 and Glu401 of FOXP3 <scene name='Forkhead_Box_Protein_3/Basic_chain/5'>interact with a string of basic residues</scene> 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.<ref name="Chen"/> The <scene name='Forkhead_Box_Protein_3/Oligo_dimer_overview/1'>FOXP3 monomers</scene> utilize their DNA binding helices to bind unique sequences within the IL-2 promoter. These helices fit within the major groove of the IL-2 promoter (<scene name='Forkhead_Box_Protein_3/Helix_2/2'>Helix 1</scene> and <scene name='Forkhead_Box_Protein_3/Oligo_dimer_overview/3'>Helix 2</scene>), primarily using FOXP3 residues <scene name='Forkhead_Box_Protein_3/Oligo_binding/2'>Thr380, Asn383, Arg386, His387, and Ser390</scene>. These oligonucletodies are held in an antiparllel conformation, making FOXP3 unable to bind nearby FOXP3 binding sites, due to steric hindrance.<ref name="Chen"/>
-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.<ref name="Chen"/>
+&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>.
-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.<ref name="Chen"/> 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<sup>+</sup> cells.<ref name="Chen"/>
+&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<sup>+</sup> 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"/>
-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.<ref name="Chen"/>
-<ref name="Chen"/>
-Talk about alignment with [[FOXP2]] and fix the morph.
 </StructureSection>