T cell tolerance induction / positive regulation of peripheral T cell tolerance induction / CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment / tolerance induction / establishment of endothelial blood-brain barrier / positive regulation of CD4-positive, alpha-beta T cell differentiation / negative regulation of alpha-beta T cell proliferation / response to rapamycin / alpha-beta T cell proliferation / negative regulation of interleukin-4 production ...T cell tolerance induction / positive regulation of peripheral T cell tolerance induction / CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment / tolerance induction / establishment of endothelial blood-brain barrier / positive regulation of CD4-positive, alpha-beta T cell differentiation / negative regulation of alpha-beta T cell proliferation / response to rapamycin / alpha-beta T cell proliferation / negative regulation of interleukin-4 production / negative regulation of CREB transcription factor activity / RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) / CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation / negative regulation of T cell cytokine production / transforming growth factor beta1 production / regulatory T cell differentiation / negative regulation of interleukin-5 production / regulation of isotype switching to IgG isotypes / tolerance induction to self antigen / negative regulation of defense response to virus / negative regulation of chronic inflammatory response / negative regulation of lymphocyte proliferation / T cell anergy / positive regulation of T cell anergy / positive regulation of transforming growth factor beta1 production / lymphocyte proliferation / immature T cell proliferation in thymus / positive regulation of T cell tolerance induction / negative regulation of T-helper 17 cell differentiation / negative regulation of isotype switching to IgE isotypes / isotype switching to IgE isotypes / CD4-positive, alpha-beta T cell proliferation / CD4-positive, alpha-beta T cell differentiation / T cell mediated immunity / positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation / positive regulation of immature T cell proliferation in thymus / negative regulation of immune response / negative regulation of CD4-positive, alpha-beta T cell proliferation / positive regulation of regulatory T cell differentiation / negative regulation of interleukin-17 production / regulation of immunoglobulin production / regulation of T cell anergy / negative regulation of cytokine production / myeloid cell homeostasis / negative regulation of interleukin-2 production / histone acetyltransferase binding / negative regulation of interleukin-10 production / negative regulation of NF-kappaB transcription factor activity / NFAT protein binding / positive regulation of interleukin-4 production / negative regulation of interleukin-6 production / B cell homeostasis / negative regulation of type II interferon production / negative regulation of tumor necrosis factor production / T cell proliferation / negative regulation of T cell proliferation / T cell activation / response to virus / negative regulation of DNA-binding transcription factor activity / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / histone deacetylase binding / transcription corepressor activity / T cell receptor signaling pathway / gene expression / DNA-binding transcription activator activity, RNA polymerase II-specific / sequence-specific DNA binding / transcription by RNA polymerase II / response to lipopolysaccharide / DNA-binding transcription factor activity, RNA polymerase II-specific / chromatin remodeling / inflammatory response / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of cell population proliferation / negative regulation of gene expression / negative regulation of DNA-templated transcription / DNA-templated transcription / positive regulation of gene expression / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding / nucleus / metal ion binding / cytoplasm / cytosol 類似検索 - 分子機能
: / FOXP, coiled-coil domain / FOXP coiled-coil domain / Fork head domain / Forkhead domain / Fork head domain profile. / FORKHEAD / Fork head domain conserved site 2 / Fork head domain signature 2. / Zinc finger C2H2 type domain signature. ...: / FOXP, coiled-coil domain / FOXP coiled-coil domain / Fork head domain / Forkhead domain / Fork head domain profile. / FORKHEAD / Fork head domain conserved site 2 / Fork head domain signature 2. / Zinc finger C2H2 type domain signature. / Zinc finger C2H2-type / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily 類似検索 - ドメイン・相同性
ジャーナル: Nature / 年: 2023 タイトル: FOXP3 recognizes microsatellites and bridges DNA through multimerization. 著者: Wenxiang Zhang / Fangwei Leng / Xi Wang / Ricardo N Ramirez / Jinseok Park / Christophe Benoist / Sun Hur / 要旨: FOXP3 is a transcription factor that is essential for the development of regulatory T cells, a branch of T cells that suppress excessive inflammation and autoimmunity. However, the molecular ...FOXP3 is a transcription factor that is essential for the development of regulatory T cells, a branch of T cells that suppress excessive inflammation and autoimmunity. However, the molecular mechanisms of FOXP3 remain unclear. Here we here show that FOXP3 uses the forkhead domain-a DNA-binding domain that is commonly thought to function as a monomer or dimer-to form a higher-order multimer after binding to TG repeat microsatellites. The cryo-electron microscopy structure of FOXP3 in a complex with TG repeats reveals a ladder-like architecture, whereby two double-stranded DNA molecules form the two 'side rails' bridged by five pairs of FOXP3 molecules, with each pair forming a 'rung'. Each FOXP3 subunit occupies TGTTTGT within the repeats in a manner that is indistinguishable from that of FOXP3 bound to the forkhead consensus motif (TGTTTAC). Mutations in the intra-rung interface impair TG repeat recognition, DNA bridging and the cellular functions of FOXP3, all without affecting binding to the forkhead consensus motif. FOXP3 can tolerate variable inter-rung spacings, explaining its broad specificity for TG-repeat-like sequences in vivo and in vitro. Both FOXP3 orthologues and paralogues show similar TG repeat recognition and DNA bridging. These findings therefore reveal a mode of DNA recognition that involves transcription factor homomultimerization and DNA bridging, and further implicates microsatellites in transcriptional regulation and diseases.