7tdx
From Proteopedia
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==Structure of FOXP3-DNA complex== | ==Structure of FOXP3-DNA complex== | ||
| - | <StructureSection load='7tdx' size='340' side='right'caption='[[7tdx]]' scene=''> | + | <StructureSection load='7tdx' size='340' side='right'caption='[[7tdx]], [[Resolution|resolution]] 3.10Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TDX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TDX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7tdx]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TDX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TDX FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7tdx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tdx OCA], [https://pdbe.org/7tdx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tdx RCSB], [https://www.ebi.ac.uk/pdbsum/7tdx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tdx ProSAT]</span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.1Å</td></tr> |
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7tdx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tdx OCA], [https://pdbe.org/7tdx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tdx RCSB], [https://www.ebi.ac.uk/pdbsum/7tdx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tdx ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/FOXP3_MOUSE FOXP3_MOUSE] Defects in Foxp3 are the cause of the scurfy phenotype (sf). It results in a lethal disorder of immunoregulation, characterized by infections, diarrhea, anemia, thrombocytopenia, hypogonadism, gastrointestinal bleeding, lymphadenopathy and leukocytosis. | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/FOXP3_MOUSE FOXP3_MOUSE] Transcriptional regulator which is crucial for the development and inhibitory function of regulatory T-cells (Treg). Plays an essential role in maintaining homeostasis of the immune system by allowing the acquisition of full suppressive function and stability of the Treg lineage, and by directly modulating the expansion and function of conventional T-cells. Can act either as a transcriptional repressor or a transcriptional activator depending on its interactions with other transcription factors, histone acetylases and deacetylases. The suppressive activity of Treg involves the coordinate activation of many genes, including CTLA4 and TNFRSF18 by FOXP3 along with repression of genes encoding cytokines such as interleukin-2 (IL2) and interferon-gamma (IFNG). Inhibits cytokine production and T-cell effector function by repressing the activity of two key transcription factors, RELA and NFATC2 (PubMed:15790681). Mediates transcriptional repression of IL2 via its association with histone acetylase KAT5 and histone deacetylase HDAC7 (By similarity). Can activate the expression of TNFRSF18, IL2RA and CTLA4 and repress the expression of IL2 and IFNG via its association with transcription factor RUNX1 (PubMed:17377532). Inhibits the differentiation of IL17 producing helper T-cells (Th17) by antagonizing RORC function, leading to down-regulation of IL17 expression, favoring Treg development (PubMed:18368049). Inhibits the transcriptional activator activity of RORA (By similarity). Can repress the expression of IL2 and IFNG via its association with transcription factor IKZF4 (PubMed:19696312).[UniProtKB:Q9BZS1]<ref>PMID:15790681</ref> <ref>PMID:17377532</ref> <ref>PMID:18368049</ref> <ref>PMID:19696312</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | FoxP3 is an essential transcription factor (TF) for immunologic homeostasis, but how it utilizes the common forkhead DNA-binding domain (DBD) to perform its unique function remains poorly understood. We here demonstrated that unlike other known forkhead TFs, FoxP3 formed a head-to-head dimer using a unique linker (Runx1-binding region [RBR]) preceding the forkhead domain. Head-to-head dimerization conferred distinct DNA-binding specificity and created a docking site for the cofactor Runx1. RBR was also important for proper folding of the forkhead domain, as truncation of RBR induced domain-swap dimerization of forkhead, which was previously considered the physiological form of FoxP3. Rather, swap-dimerization impaired FoxP3 function, as demonstrated with the disease-causing mutation R337Q, whereas a swap-suppressive mutation largely rescued R337Q-mediated functional impairment. Altogether, our findings suggest that FoxP3 can fold into two distinct dimerization states: head-to-head dimerization representing functional specialization of an ancient DBD and swap dimerization associated with impaired functions. | ||
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| + | The transcription factor FoxP3 can fold into two dimerization states with divergent implications for regulatory T cell function and immune homeostasis.,Leng F, Zhang W, Ramirez RN, Leon J, Zhong Y, Hou L, Yuki K, van der Veeken J, Rudensky AY, Benoist C, Hur S Immunity. 2022 Aug 9;55(8):1354-1369.e8. doi: 10.1016/j.immuni.2022.07.002. Epub , 2022 Aug 3. PMID:35926508<ref>PMID:35926508</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7tdx" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| + | [[Category: Mus musculus]] | ||
[[Category: Hur S]] | [[Category: Hur S]] | ||
[[Category: Leng F]] | [[Category: Leng F]] | ||
Current revision
Structure of FOXP3-DNA complex
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