FOXP3 recognizes microsatellites and bridges DNA through multimerization.
FOXP3 recognizes microsatellites and bridges DNA through multimerization.
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DOI：
10.1038/s41586-023-06793-z
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发表时间：
2023-12
期刊：
影响因子：
64.8
通讯作者：
Hur, Sun
中科院分区：
文献类型：
--
作者：
Zhang, Wenxiang;Leng, Fangwei;Wang, Xi;Ramirez, Ricardo N.;Park, Jinseok;Benoist, Christophe;Hur, Sun
FOXP3是一种转录因子，对调节性T细胞的发育至关重要，调节性T细胞是抑制过度炎症和自身免疫的T细胞的分支。然而，FOXP3的分子机制仍不清楚。在这里，我们表明FOXP 3使用叉头结构域（一种通常被认为具有单体或二聚体功能的DNA结合结构域）在与TnG重复微卫星结合后形成更高级的多聚体。FOXP3与T3G重复复合物的冷冻电子显微镜结构揭示了一种梯状结构，其中两个双链DNA分子形成由五对FOXP3分子桥接的两个“侧轨”，每对形成一个“梯级”。每个FOXP3亚基在重复序列中占据TGTTTGT，其方式与FOXP3与叉头共有基序（TGTTTAC）结合的方式无法区分。梯级内界面的突变损害TnG重复识别、DNA桥接和FOXP3的细胞功能，所有这些都不影响与叉头共有基序的结合。FOXP3可以容忍可变的梯级间距，解释其广泛的特异性TnG重复序列在体内和体外。FOXP3直向同源物和旁系同源物都显示出相似的TnG重复识别和DNA桥接。因此，这些发现揭示了一种涉及转录因子同源多聚化和DNA桥接的DNA识别模式，并进一步暗示微卫星在转录调控和疾病中的作用。FOXP3在与TnG重复微卫星结合后，利用叉头结构域形成高阶多聚体。
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 TnG repeat microsatellites. The cryo-electron microscopy structure of FOXP3 in a complex with T3G 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 TnG 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 TnG-repeat-like sequences in vivo and in vitro. Both FOXP3 orthologues and paralogues show similar TnG 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 uses the forkhead domain to form a higher-order multimer after binding to TnG repeat microsatellites.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
DOI：
10.1126/science.1162327
发表时间：
2009-06-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badis G;Berger MF;Philippakis AA;Talukder S;Gehrke AR;Jaeger SA;Chan ET;Metzler G;Vedenko A;Chen X;Kuznetsov H;Wang CF;Coburn D;Newburger DE;Morris Q;Hughes TR;Bulyk ML
通讯作者：
Bulyk ML
影响因子：
30.5
作者：
Kitagawa Y;Ohkura N;Kidani Y;Vandenbon A;Hirota K;Kawakami R;Yasuda K;Motooka D;Nakamura S;Kondo M;Taniuchi I;Kohwi-Shigematsu T;Sakaguchi S
通讯作者：
Sakaguchi S
DOI：
10.1042/bcj20210708
发表时间：
2021-12-22
期刊：
The Biochemical journal
影响因子：
--
作者：
Kimanius D;Dong L;Sharov G;Nakane T;Scheres SHW
通讯作者：
Scheres SHW
影响因子：
4.6
作者：
Bonneville R;Krook MA;Kautto EA;Miya J;Wing MR;Chen HZ;Reeser JW;Yu L;Roychowdhury S
通讯作者：
Roychowdhury S