FMR1 KH0-KH1结构域在脆性X综合征中协调m6A结合和相分离

IF 3.5 3区 生物学 Q3 CELL BIOLOGY
Xian Zhou , Chen-Jun Guo , Rui Wang , Yi-Lan Li , Tianyi Zhang , Zhuangyi Qiu , Shaorong Gao , Ji-Long Liu , Yawei Gao
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引用次数: 0

摘要

脆弱的X信使核糖核蛋白1 (FMR1)通过m6A RNA相互作用调节神经发育,但KH0和KH1在RNA结合和疾病发病机制中的结构域特异性作用仍然知之甚少。通过诱变和AlphaFold3结构建模,我们确定KH1是主要的m6a结合界面,而KH0结构域(特别是Arg138)调节液-液相分离(LLPS)。KH0的致病性突变损害RNA结合并促进LLPS的异常聚集,而m6a修饰的RNA抑制KH0的LLPS形成。结构模拟揭示了由疏水和静电网络介导的KH0和KH1之间的协同相互作用。这些特定区域的合作建立了m6A失调、病理相分离和脆性X综合征发病机制之间的机制联系。我们的研究结果表明KH0是rna驱动的神经发育障碍的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
FMR1 KH0-KH1 domains coordinate m6A binding and phase separation in Fragile X syndrome
Fragile X messenger ribonucleoprotein 1 (FMR1) regulates neurodevelopment through m6A RNA interactions, yet the domain-specific roles of KH0 and KH1 in RNA binding and disease pathogenesis remain poorly understood. Using mutagenesis and AlphaFold3 structural modeling, we identify KH1 as the primary m6A-binding interface, while the KH0 domain (particularly Arg138) modulates liquid-liquid phase separation (LLPS). Pathogenic mutations in KH0 impair RNA binding and promote aberrant LLPS aggregation, whereas m6A-modified RNA suppresses LLPS formation at KH0. Structural simulations uncover synergistic interactions between KH0 and KH1 mediated by hydrophobic and electrostatic networks. These domain-specific cooperations establish a mechanistic link between m6A dysregulation, pathological phase separation, and Fragile X syndrome pathogenesis. Our findings nominate KH0 as a potential therapeutic target for RNA-driven neurodevelopmental disorders.
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来源期刊
Experimental cell research
Experimental cell research 医学-细胞生物学
CiteScore
7.20
自引率
0.00%
发文量
295
审稿时长
30 days
期刊介绍: Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.
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