8srp
FoxP3 forms Ladder-like multimer to bridge TTTG repeats
Structural highlights
DiseaseFOXP3_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. FunctionFOXP3_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][1] [2] [3] [4] Publication Abstract from PubMedFOXP3 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(1-5). 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 T(n)G repeat microsatellites. The cryo-electron microscopy structure of FOXP3 in a complex with T(3)G 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 T(n)G 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 T(n)G-repeat-like sequences in vivo and in vitro. Both FOXP3 orthologues and paralogues show similar T(n)G 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. FOXP3 recognizes microsatellites and bridges DNA through multimerization.,Zhang W, Leng F, Wang X, Ramirez RN, Park J, Benoist C, Hur S Nature. 2023 Dec;624(7991):433-441. doi: 10.1038/s41586-023-06793-z. Epub 2023 , Nov 29. PMID:38030726[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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