Safari Mohammad S, Wang Zhiqing, Tailor Kunaal, Kolomeisky Anatoly B, Conrad Jacinta C, Vekilov Peter G
Department of Chemical and Biomolecular Engineering, University of Houston, 4726 Calhoun Road, Houston, TX 77204-4004, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544-1014, USA.
Department of Chemical and Biomolecular Engineering, University of Houston, 4726 Calhoun Road, Houston, TX 77204-4004, USA.
iScience. 2019 Feb 22;12:342-355. doi: 10.1016/j.isci.2019.01.027. Epub 2019 Jan 24.
About half of human cancers are associated with mutations of the tumor suppressor p53. Gained oncogenic functions of the mutants have been related to aggregation behaviors of wild-type and mutant p53. The thermodynamic and kinetic mechanisms of p53 aggregation are poorly understood. Here we find that wild-type p53 forms an anomalous liquid phase. The liquid condensates exhibit several behaviors beyond the scope of classical phase transition theories: their size, ca. 100 nm, is independent of the p53 concentration and decoupled from the protein mass held in the liquid phase. Furthermore, the liquid phase lacks constant solubility. The nucleation of p53 fibrils deviates from the accepted mechanism of sequential association of single solute molecules. We find that the liquid condensates serve as pre-assembled precursors of high p53 concentration that facilitate fibril assembly. Fibril nucleation hosted by precursors represents a novel biological pathway, which opens avenues to suppress protein fibrillation in aggregation diseases.
大约一半的人类癌症与肿瘤抑制因子p53的突变有关。突变体获得的致癌功能与野生型和突变型p53的聚集行为有关。p53聚集的热力学和动力学机制尚不清楚。在这里，我们发现野生型p53形成了一种异常的液相。液体凝聚物表现出几种超出经典相变理论范围的行为：它们的大小约为100纳米，与p53浓度无关，并且与液相中的蛋白质质量解耦。此外，液相缺乏恒定的溶解度。p53原纤维的成核偏离了单个溶质分子顺序缔合的公认机制。我们发现液体凝聚物作为高p53浓度的预组装前体，促进原纤维组装。由前体介导的原纤维成核代表了一种新的生物学途径，为抑制聚集疾病中的蛋白质纤维化开辟了道路。
