Forkhead Box Protein 3: Difference between revisions

← Older edit

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Alexander Berchansky, David Canner

@@ Line 4: / Line 4: @@
 &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 such as **F371C, F373A and R347H** are known to occur in IPEX patients. Phe373 is **buried within the hydrophobic core** 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 **angled away from the dimer interface** and thus probably does not play a critical role in dimer formation, but rather might disrupt overall FOXP3 function. Since the **R347H mutation** has been shown to not interfere with DNA binding, but still eliminates FOXP3 function, it likely interferes with FOXP3 dimerization capacity. 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 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"/>
+&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"/>
 </StructureSection>