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Structural Basis for DNA Recognition by FOXG1 and the Characterization of Disease-causing FOXG1 Mutations
Journal of Molecular Biology ( IF 4.7 ) Pub Date : 2020-10-13 , DOI: 10.1016/j.jmb.2020.10.007
Shuyan Dai , Jun Li , Huajun Zhang , Xiaojuan Chen , Ming Guo , Zhuchu Chen , Yongheng Chen

Forkhead box G1 (FOXG1) is a transcription factor mainly expressed in the brain that plays a critical role in the development and regionalization of the forebrain. Aberrant expression of FOXG1 has implications in FOXG1 syndrome, a serious neurodevelopmental disorder. Here, we report the crystal structure of the FOXG1 DNA-binding domain (DBD) in complex with the forkhead consensus DNA site DBE2 at the resolution of 1.6 Å. FOXG1-DBD adopts a typical winged helix fold. Compared to those of other FOX-DBD/DBE2 structures, the N terminus, H3 helix and wing2 region of FOXG1-DBD exhibit differences in DNA recognition. The FOXG1-DBD wing2 region adopts a unique architecture composed of two β-strands that differs from all other known FOX-DBD wing2 folds. Mutation assays revealed that the disease-causing mutations within the FOXG1-DBD affect DNA binding, protein thermal stability, or both. Our report provides initial insight into how FOXG1 binds DNA and sheds light on how disease-causing mutations in FOXG1-DBD affect its DNA-binding ability.



中文翻译:

FOXG1识别DNA的结构基础和致病性FOXG1突变的表征

叉头盒G1(FOXG1)是主要在大脑中表达的转录因子,在前脑的发育和区域化中起关键作用。FOXG1的异常表达与FOXG1综合征(一种严重的神经发育障碍)有关。在这里,我们报告了与叉头共有DNA位点DBE2复杂的FOXG1 DNA结合域(DBD)的晶体结构,分辨率为1.6。FOXG1-DBD采用典型的带翼螺旋褶皱。与其他FOX-DBD / DBE2结构相比,FOXG1-DBD的N末端,H3螺旋和wing2区域在DNA识别方面表现出差异。FOXG1-DBD wing2区域采用独特的架构,该架构由两条β链组成,这不同于所有其他已知的FOX-DBD wing2折叠。突变分析显示,FOXG1-DBD内部的致病突变会影响DNA结合,蛋白质热稳定性,或两者兼而有之。我们的报告提供了有关FOXG1如何结合DNA的初步见解,并阐明了FOXG1-DBD中的致病突变如何影响其DNA结合能力。

更新日期:2020-11-23
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