Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany; Max Planck Institute for the Physics of Complex Systems, 01187 Dresden, Germany.
Cell. 2015 Aug 27;162(5):1066-77. doi: 10.1016/j.cell.2015.07.047.
Many proteins contain disordered regions of low-sequence complexity, which cause aging-associated diseases because they are prone to aggregate. Here, we study FUS, a prion-like protein containing intrinsically disordered domains associated with the neurodegenerative disease ALS. We show that, in cells, FUS forms liquid compartments at sites of DNA damage and in the cytoplasm upon stress. We confirm this by reconstituting liquid FUS compartments in vitro. Using an in vitro "aging" experiment, we demonstrate that liquid droplets of FUS protein convert with time from a liquid to an aggregated state, and this conversion is accelerated by patient-derived mutations. We conclude that the physiological role of FUS requires forming dynamic liquid-like compartments. We propose that liquid-like compartments carry the trade-off between functionality and risk of aggregation and that aberrant phase transitions within liquid-like compartments lie at the heart of ALS and, presumably, other age-related diseases.
许多蛋白质含有低序列复杂度的无序区域，这些区域容易聚集，从而导致与衰老相关的疾病。在这里，我们研究了 FUS，它是一种朊病毒样蛋白，含有与神经退行性疾病 ALS 相关的内在无序结构域。我们发现，在细胞中，FUS 在 DNA 损伤部位和应激时的细胞质中形成液体隔室。我们通过在体外重新构建液体 FUS 隔室来证实这一点。通过体外“老化”实验，我们证明 FUS 蛋白的液滴随时间从液态转变为聚集态，并且这种转变被患者衍生的突变加速。我们得出结论，FUS 的生理作用需要形成动态的类似液体的隔室。我们提出，类似液体的隔室具有功能和聚集风险之间的权衡，并且类似液体的隔室中的异常相转变是 ALS 以及推测的其他与年龄相关的疾病的核心所在。
