Several aggregation-prone RNA-binding proteins, including FUS, EWS, TAF15, hnRNP A1, hnRNP A2, and TDP-43, are mutated in neurodegenerative diseases. The nuclear-cytoplasmic distribution of these proteins is controlled by proteins in the karyopherin family of nuclear transport factors (Kaps). Recent studies have shown that Kaps not only transport these proteins but also inhibit their self-association/aggregation, acting as molecular chaperones. This chaperone activity is impaired for disease-causing mutants of the RNA-binding proteins. Here, we review physical data on the mechanisms of self-association of several disease-associated RNA-binding proteins, through liquid-liquid phase separation and amyloid fiber formation. In each case, we relate these data to biophysical, biochemical, and cell biological data on the inhibition of self-association by Kaps. Our analyses suggest that Kaps may be effective chaperones because they contain large surfaces with diverse physical properties that enable them to engage multiple different regions of their cargo proteins, blocking self-association.

中文翻译：

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核转运蛋白和冷凝物。

几种易于聚集的 RNA 结合蛋白，包括 FUS、EWS、TAF15、hnRNP A1、hnRNP A2 和 TDP-43，在神经退行性疾病中发生突变。这些蛋白质的核质分布受核转运因子 (Kaps) 核转运蛋白家族中的蛋白质控制。最近的研究表明，Kaps 不仅可以运输这些蛋白质，还可以抑制它们的自缔合/聚集，充当分子伴侣。对于 RNA 结合蛋白的致病突变体，这种伴侣活性受到损害。在这里，我们回顾了几种疾病相关 RNA 结合蛋白通过液-液相分离和淀粉样蛋白纤维形成的自缔合机制的物理数据。在每种情况下，我们都将这些数据与生物物理、生化、和关于 Kaps 抑制自我关联的细胞生物学数据。我们的分析表明，Kaps 可能是有效的伴侣，因为它们包含具有不同物理特性的大表面，使它们能够接合其货物蛋白的多个不同区域，从而阻止自我关联。