Loss of Dynamic RNA Interaction and Aberrant Phase Separation Induced by Two Distinct Types of ALS/FTD-Linked FUS Mutations
Loss of Dynamic RNA Interaction and Aberrant Phase Separation Induced by Two Distinct Types of ALS/FTD-Linked FUS Mutations
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DOI：
10.1016/j.molcel.2019.09.022
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发表时间：
2020-01-02
期刊：
影响因子：
16
通讯作者：
Myong, Sua
中科院分区：
文献类型：
--
作者：
Niaki, Amirhossein Ghanbari;Sarkar, Jaya;Myong, Sua
FUS 是一种核 RNA 结合蛋白，其细胞质聚集是肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 的致病特征。目前尚不清楚 FUS-RNA 相互作用如何促进相分离以及其相行为是否受到 ALS 相关突变的影响。在这里，我们证明野生型 FUS 以长度依赖的方式化学计量地结合单链 RNA，并且多聚体诱导与 RNA 的高度动态相互作用，产生小且流体的冷凝物。相比之下，精氨酸的突变表现出严重改变的构象、与RNA的静态结合以及大凝聚物的形成，这表明精氨酸在驱动适当的RNA相互作用中的作用。甘氨酸突变会导致流动性迅速丧失，强调了甘氨酸在促进流动性方面的作用。引人注目的是，核输入受体 Karyopherin-beta 2 逆转了突变缺陷并恢复了野生型 FUS 行为。我们揭示了两种不同的机制支撑 ALS 相关 FUS 突变体潜在不同的致病途径。
FUS is a nuclear RNA-binding protein, and its cytoplasmic aggregation is a pathogenic signature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It remains unknown how the FUS-RNA interactions contribute to phase separation and whether its phase behavior is affected by ALS-linked mutations. Here we demonstrate that wild-type FUS binds single-stranded RNA stoichiometrically in a length-dependent manner and that multimers induce highly dynamic interactions with RNA, giving rise to small and fluid condensates. In contrast, mutations in arginine display a severely altered conformation, static binding to RNA, and formation of large condensates, signifying the role of arginine in driving proper RNA interaction. Glycine mutations undergo rapid loss of fluidity, emphasizing the role of glycine in promoting fluidity. Strikingly, the nuclear import receptor Karyopherin-beta 2 reverses the mutant defects and recovers the wild-type FUS behavior. We reveal two distinct mechanisms underpinning potentially disparate pathogenic pathways of ALS-linked FUS mutants.