RNA-binding proteins with prion-like domains in health and disease.
RNA-binding proteins with prion-like domains in health and disease.
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DOI：
10.1042/bcj20160499
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发表时间：
2017-04-07
期刊：
影响因子：
--
通讯作者：
Shorter J
中科院分区：
文献类型：
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作者：
Harrison AF;Shorter J
大约70种人RNA结合蛋白（RBP）含有朊病毒样结构域（PrLD）。PrLD是低复杂性结构域，其具有与酵母中的朊病毒结构域相似的氨基酸组成，这使得包括Sup 35和Rnq 1在内的几种蛋白质能够形成称为朊病毒的感染性构象异构体。在人类中，PrLD有助于RBP功能，并使RBP能够经历液-液相转变，这是各种无膜细胞器生物发生的基础。然而，这种活性似乎使RBP易于发生与神经退行性疾病相关的错误折叠和聚集。事实上，包括TDP-43在内的许多含PrLD的RBP（反式激活反应元件DNA结合蛋白43），FUS（融合于肉瘤），TAF 15（TATA结合蛋白相关因子15），EWSR 1（尤文肉瘤断点区1）和异质核核糖核蛋白A1和A2（hnRNPA 1和hnRNPA 2），现在已经通过病理学和遗传学与几种神经退行性疾病的病因学相关联，包括肌萎缩性侧索硬化，额颞叶痴呆，和多系统蛋白质病。在这里，我们审查的生理和病理作用的最突出的RBP与PrLD。我们还强调了蛋白解聚剂（包括Hsp 104）作为治疗策略的潜力，以对抗可能支持神经退行性变的RBP与PrLD的异常相变。
Approximately 70 human RNA-binding proteins (RBPs) contain a prion-like domain (PrLD). PrLDs are low-complexity domains that possess a similar amino acid composition to prion domains in yeast, which enable several proteins, including Sup35 and Rnq1, to form infectious conformers, termed prions. In humans, PrLDs contribute to RBP function and enable RBPs to undergo liquid–liquid phase transitions that underlie the biogenesis of various membraneless organelles. However, this activity appears to render RBPs prone to misfolding and aggregation connected to neurodegenerative disease. Indeed, numerous RBPs with PrLDs, including TDP-43 (transactivation response element DNA-binding protein 43), FUS (fused in sarcoma), TAF15 (TATA-binding protein-associated factor 15), EWSR1 (Ewing sarcoma breakpoint region 1), and heterogeneous nuclear ribo-nucleoproteins A1 and A2 (hnRNPA1 and hnRNPA2), have now been connected via pathology and genetics to the etiology of several neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Here, we review the physiological and pathological roles of the most prominent RBPs with PrLDs. We also highlight the potential of protein disaggregases, including Hsp104, as a therapeutic strategy to combat the aberrant phase transitions of RBPs with PrLDs that likely underpin neurodegeneration.