Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Biophysics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Curr Opin Cell Biol. 2020 Jun;64:112-123. doi: 10.1016/j.ceb.2020.04.003. Epub 2020 May 28.
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.
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）家族中的核蛋白的控制。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我结合/聚集，起到分子伴侣的作用。这种伴侣活性对于 RNA 结合蛋白的致病突变体受损。在这里，我们通过液-液相分离和淀粉样纤维形成，回顾了几种与疾病相关的 RNA 结合蛋白的自我结合机制的物理数据。在每种情况下，我们都将这些数据与 Kaps 抑制自我结合的生物物理、生化和细胞生物学数据联系起来。我们的分析表明，Kaps 可能是有效的伴侣，因为它们含有大的表面，具有不同的物理特性，使它们能够与货物蛋白的多个不同区域结合，从而阻止自身聚集。
