A predictive coarse-grained model for position-specific effects of post-translational modifications
A predictive coarse-grained model for position-specific effects of post-translational modifications
复制标题
一个预测翻译后修饰的位置特异性效应的粗粒度模型
DOI：
10.1016/j.bpj.2021.01.034
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发表时间：
2021-04-06
影响因子：
3.4
通讯作者：
Mittal, Jeetain
中科院分区：
文献类型：
--
作者：
Perdikari, Theodora Myrto;Jovic, Nina;Mittal, Jeetain
生物分子经历液-液相分离（LLPS），导致细胞中多组分蛋白质-RNA无膜细胞器的形成。然而，生理和病理作用的翻译后修饰（PTM）的生物物理学的相位行为才刚刚开始被探讨。为了研究PTM对LLPS的影响，我们扩展了我们的可转移粗粒度模型的内在无序蛋白质，包括磷酸化和乙酰化氨基酸。使用固定电荷原子力场的改性氨基酸的参数，我们parameterized的粗粒改性氨基酸珠的大小和原子亲水性，因此，改性和天然氨基酸之间的相互作用。然后，我们阐明了磷酸化和乙酰化残基的数量和位置如何改变蛋白质的单链紧凑性和相分离的倾向。我们发现，磷酸化的苏氨酸/丝氨酸或乙酰化赖氨酸的数量和位置可以作为一个分子的开/关开关相分离在融合的肉瘤（FUS）和DDX 3X，分别研究的无序区域。我们还比较了修饰的残基，其常用的PTM模拟物的链特性的影响。重要的是，我们表明该模型可以预测和捕获位置特定修饰的相行为的实验测量差异，表明修饰的位置可以决定相分离。总之，这个模型将是有用的研究后修饰的内在无序蛋白质的LLPS和预测修饰如何控制相位行为与位置特定的分辨率。
Biomolecules undergo liquid-liquid phase separation (LLPS), resulting in the formation of multicomponent protein-RNA membraneless organelles in cells. However, the physiological and pathological role of post-translational modifications (PTMs) on the biophysics of phase behavior is only beginning to be probed. To study the effect of PTMs on LLPS in silico, we extend our transferable coarse-grained model of intrinsically disordered proteins to include phosphorylated and acetylated amino acids. Using the parameters for modified amino acids available for fixed-charge atomistic force fields, we parameterize the size and atomistic hydropathy of the coarse-grained-modified amino acid beads and, hence, the interactions between the modified and natural amino acids. We then elucidate how the number and position of phosphorylated and acetylated residues alter the protein's single-chain compactness and its propensity to phase separate. We show that both the number and the position of phosphorylated threonines/serines or acetylated lysines can serve as a molecular on/off switch for phase separation in the well-studied disordered regions of Fused in Sarcoma (FUS) and DDX3X, respectively. We also compare modified residues to their commonly used PTM mimics for their impact on chain properties. Importantly, we show that the model can predict and capture experimentally measured differences in the phase behavior for position-specific modifications, showing that the position of modifications can dictate phase separation. In sum, this model will be useful for studying LLPS of post-translationally modified intrinsically disordered proteins and predicting how modifications control phase behavior with position-specific resolution.