The physics of liquid-to-solid transitions in multi-domain protein condensates.
The physics of liquid-to-solid transitions in multi-domain protein condensates.
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多域蛋白质凝聚物中液体到固体转变的物理学。
DOI：
10.1016/j.bpj.2022.06.013
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发表时间：
2022
影响因子：
3.4
通讯作者：
Shakhnovich,Eugene
中科院分区：
文献类型：
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作者：
Ranganathan,Srivastav;Shakhnovich,Eugene
许多组装成无膜细胞器的 RNA 结合蛋白 (RBP) 具有共同的结构，包括无序的朊病毒样结构域 (PLD) 和折叠的 RNA 结合结构域 (RBD)。 PLD 在凝聚相中的富集导致在较长时间尺度上形成类淀粉样原纤维（老化）。在本研究中，我们采用粗粒度朗之万动力学模拟来探索多域 RBP 凝聚相结构多样性的物理基础。我们发现无序结构和有序相之间存在高度协作的一阶转变，由此 PLD 链以高向列取向顺序组织成原纤维。同域（PLD-PLD）和异域（PLD-RBD）之间的相互作用导致了具有不同空间架构的各种结构。有趣的是，不同的结构相还表现出截然不同的蛋白质簇内动力学，其扩散系数比稀相低5倍（无序结构）至50倍（有序结构）。这种液-固转变的协同作用使得原纤维的形成对突变或翻译后修饰具有高度的可塑性。我们的结果提供了对多域 RBP 如何形成具有不同结构和材料特性的组件的机械理解。
Many RNA-binding proteins (RBPs) that assemble into membraneless organelles have a common architecture including disordered prion-like domain (PLD) and folded RNA-binding domain (RBD). An enrichment of PLD within the condensed phase gives rise to formation, on longer time scales, of amyloid-like fibrils (aging). In this study, we employ coarse-grained Langevin dynamics simulations to explore the physical basis for the structural diversity in condensed phases of multi-domain RBPs. We discovered a highly cooperative first-order transition between disordered structures and an ordered phase whereby chains of PLD organize in fibrils with high nematic orientational order. An interplay between homodomain (PLD-PLD) and heterodomain (PLD-RBD) interactions results in variety of structures with distinct spatial architectures. Interestingly, the different structural phases also exhibit vastly different intracluster dynamics of proteins, with diffusion coefficients 5 times (disordered structures) to 50 times (ordered structures) lower than that of the dilute phase. Cooperativity of this liquid-solid transition makes fibril formation highly malleable to mutations or post-translational modifications. Our results provide a mechanistic understanding of how multi-domain RBPs could form assemblies with distinct structural and material properties.