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转录因子FoxP3可折叠成两种二聚体状态
作者:小柯机器人 发布时间:2022/8/6 23:43:33

美国波士顿儿童医院Sun Hur团队近期取得了重要工作进展,他们研究发现转录因子FoxP3可以折叠成两种二聚体状态,对调节性T细胞功能和免疫稳态有不同的影响。相关论文于2022年8月3日在线发表于《免疫》杂志上。

研究人员证明,与其他已知的叉头TF不同,FoxP3在叉头域之前使用独特的接头(Runx1 结合区 [RBR])形成了一个头对头的二聚体。头对头二聚化赋予了独特的DNA结合特异性,并为辅因子Runx1创建了一个对接位点。RBR对于叉头结构域的正确折叠也很重要,因为RBR的截断诱导叉头的结构域交换二聚化,这以前被认为是FoxP3的生理形式。相反,交换二聚化损害了FoxP3的功能,正如致病突变R337Q所证明的那样,而交换抑制突变在很大程度上挽救了R337Q介导的功能障碍。

总而言之,他们的研究结果表明FoxP3可以折叠成两种不同的二聚化状态:代表古代DBD功能特化的头对头二聚化和与受损功能相关的交换二聚化。

据介绍,FoxP3是免疫稳态的关键转录因子(TF),但其如何利用常见的叉头DNA结合域(DBD)实现其独特功能仍不清楚。

附:英文原文

Title: The transcription factor FoxP3 can fold into two dimerization states with divergent implications for regulatory T cell function and immune homeostasis

Author: Fangwei Leng, Wenxiang Zhang, Ricardo N. Ramirez, Juliette Leon, Yi Zhong, Lifei Hou, Koichi Yuki, Joris van der Veeken, Alexander Y. Rudensky, Christophe Benoist, Sun Hur

Issue&Volume: 2022-08-03

Abstract: 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.

DOI: 10.1016/j.immuni.2022.07.002

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00335-1

期刊信息

Immunity:《免疫》,创刊于1994年。隶属于细胞出版社,最新IF:21.522
官方网址:https://www.cell.com/immunity/home
投稿链接:https://www.editorialmanager.com/immunity/default.aspx