Molecular Dissection of FUS Points at Synergistic Effect of Low-Complexity Domains in Toxicity.
Molecular Dissection of FUS Points at Synergistic Effect of Low-Complexity Domains in Toxicity.
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DOI：
10.1016/j.celrep.2018.06.070
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发表时间：
2018-07-17
期刊：
影响因子：
8.8
通讯作者：
Van Den Bosch L
中科院分区：
文献类型：
--
作者：
Bogaert E;Boeynaems S;Kato M;Guo L;Caulfield TR;Steyaert J;Scheveneels W;Wilmans N;Haeck W;Hersmus N;Schymkowitz J;Rousseau F;Shorter J;Callaerts P;Robberecht W;Van Damme P;Van Den Bosch L
RNA结合蛋白聚集是几种神经退行性疾病的病理特征，包括肌萎缩侧索硬化症(ALS)和额颞叶变性(FTLD)。为了更好地了解这一过程背后的分子相互作用，我们研究了FUS，它在ALS和FTLD中突变并聚集。我们建立了FUS毒性的果蝇模型，并确定了N端Pron样结构域和C端富含精氨酸结构域之间的协同效应，以介导FUS毒性。虽然Prin样结构域通常被认为介导FUS的聚集，但我们发现，在细胞应激颗粒中，C端低复杂性结构域中的精氨酸残基也是FUS成熟所必需的。这些数据突显了富含精氨酸的结构域在RNA结合蛋白的病理中的重要作用。QGSY和RGG2结构域都是FUS诱导果蝇神经变性所必需的，富含精氨酸的结构域与QGSY水凝胶和液滴相互作用，RGG2精氨酸在体外和细胞内促进FUS的相分离，体外FUS相分离行为与体内神经变性相关，蛋白质聚集是ALS的一个标志。博加特等人。描述FUS蛋白无序区域之间的分子相互作用，驱动其液态行为、成熟和神经毒性。这些发现突出了驱动FUS相分离的物理化学相互作用，并使我们对其在疾病中的错误调控有了深入的了解。
RNA-binding protein aggregation is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To gain better insight into the molecular interactions underlying this process, we investigated FUS, which is mutated and aggregated in both ALS and FTLD. We generated a Drosophila model of FUS toxicity and identified a previously unrecognized synergistic effect between the N-terminal prion-like domain and the C-terminal arginine-rich domain to mediate toxicity. Although the prion-like domain is generally considered to mediate aggregation of FUS, we find that arginine residues in the C-terminal low-complexity domain are also required for maturation of FUS in cellular stress granules. These data highlight an important role for arginine-rich domains in the pathology of RNA-binding proteins. Both QGSY and RGG2 domains are necessary for FUS-induced neurodegeneration in flies Arginine-rich domains interact with QGSY hydrogels and liquid droplets RGG2 arginines promote phase separation of FUS in vitro and in cells FUS phase separation behavior in vitro correlates with neurodegeneration in vivo Protein aggregation is a hallmark of ALS. Bogaert et al. describe the molecular interactions between disordered regions of the FUS protein driving its liquid phase behavior, maturation, and neurotoxicity. These findings highlight the physicochemical interactions driving FUS phase separation and give us insights into its misregulation in disease.
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影响因子：
16.1
作者：
Chen, Xiaoying;Zaro, Jennica L.;Shen, Wei-Chiang
通讯作者：
Shen, Wei-Chiang
DOI：
10.1083/jcb.201302044
发表时间：
2013-04-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Li YR;King OD;Shorter J;Gitler AD
通讯作者：
Gitler AD
影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
影响因子：
6.1
作者：
Jaeckel, Sandra;Summerer, Anna K.;Kahle, Philipp J.
通讯作者：
Kahle, Philipp J.
影响因子：
19
作者：
Boeynaems S;Alberti S;Fawzi NL;Mittag T;Polymenidou M;Rousseau F;Schymkowitz J;Shorter J;Wolozin B;Van Den Bosch L;Tompa P;Fuxreiter M
通讯作者：
Fuxreiter M