Proteins such as FUS phase separate to form liquid-like condensates that can harden into less dynamic structures. However, how these properties emerge from the collective interactions of many amino acids remains largely unknown. Here, we use extensive mutagenesis to identify a sequence-encoded molecular grammar underlying the driving forces of phase separation of proteins in the FUS family and test aspects of this grammar in cells. Phase separation is primarily governed by multivalent interactions among tyrosine residues from prion-like domains and arginine residues from RNA-binding domains, which are modulated by negatively charged residues. Glycine residues enhance the fluidity, whereas glutamine and serine residues promote hardening. We develop a model to show that the measured saturation concentrations of phase separation are inversely proportional to the product of the numbers of arginine and tyrosine residues. These results suggest it is possible to predict phase-separation properties based on amino acid sequences.

中文翻译：

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分子语法控制驱动力的Pri子样RNA结合蛋白的相分离。

蛋白质（例如FUS相）会分离形成液体状的冷凝物，这些冷凝物可能会硬化成动力较弱的结构。但是，这些性质如何从许多氨基酸的集体相互作用中显现出来的，在很大程度上仍然未知。在这里，我们使用广泛的诱变来识别FUS家族中蛋白质相分离的驱动力背后的序列编码分子语法，并在细胞中测试该语法的各个方面。相分离主要受病毒样结构域的酪氨酸残基与RNA结合结构域的精氨酸残基之间多价相互作用的控制，这些相互作用由带负电荷的残基调节。甘氨酸残基增强流动性，而谷氨酰胺和丝氨酸残基促进硬化。我们开发了一个模型，表明所测得的相分离饱和浓度与精氨酸和酪氨酸残基数量的乘积成反比。这些结果表明可以基于氨基酸序列预测相分离特性。