Liquid network connectivity regulates the stability and composition of biomolecular condensates with many components
Liquid network connectivity regulates the stability and composition of biomolecular condensates with many components
复制标题
DOI：
10.1073/pnas.1917569117
复制
发表时间：
2020-06-16
影响因子：
11.1
通讯作者：
Collepardo-Guevara, Rosana
中科院分区：
文献类型：
--
作者：
Espinosa, Jorge R.;Joseph, Jerelle A.;Collepardo-Guevara, Rosana
细胞控制其众多组分时空组织的关键机制之一是通过液-液相分离（LLPS）形成和溶解生物分子凝聚物。使用最小的粗粒度模型，使我们能够模拟数千种相互作用的多价蛋白，我们研究了决定多组分生物分子凝聚物稳定性和组成的物理参数。我们证明了冷凝-液体网络的分子连通性。，弱吸引蛋白的数量——每单位体积的蛋白相互作用——决定了多组分凝聚物的稳定性（如温度、pH、盐浓度），其中稳定性与连通性正相关。虽然支架（LLPS必需的生物分子）的连性主导着相景观，但客户端（通过支架-客户端相互作用招募的物种）的引入通过改变支架-支架键网络对其进行微调。然而竞争支架结合位点的低价客户端会降低连接性和稳定性，而那些与LLPS不需要的替代支架位点结合或具有高于支架价的替代支架位点形成额外的支架-客户-支架桥，从而增加稳定性。建立更多连接的蛋白质（通过增加价、混杂结合和允许多价相互作用的拓扑结构）支持多组分凝聚物的稳定性，并在多组分凝聚物中富集。重要的是，增加多组分凝聚物连通性的蛋白质作为纯体系具有更高的临界点，或者，如果纯LLPS不可行的情况下，作为二元支架-客户端混合物。因此，可接近系统（即只有少数组分）的临界点可以作为预测多组分凝析物组成的统一热力学参数。
One of the key mechanisms used by cells to control the spatiotemporal organization of their many components is the formation and dissolution of biomolecular condensates through liquid-liquid phase separation (LLPS). Using a minimal coarse-grained model that allows us to simulate thousands of interacting multivalent proteins, we investigate the physical parameters dictating the stability and composition of multicomponent biomolecular condensates. We demonstrate that the molecular connectivity of the condensed-liquid network-i.e., the number of weak attractive protein-protein interactions per unit of volume-determines the stability (e.g., in temperature, pH, salt concentration) of multicomponent condensates, where stability is positively correlated with connectivity. While the connectivity of scaffolds (biomolecules essential for LLPS) dominates the phase landscape, introduction of clients (species recruited via scaffold-client interactions) fine-tunes it by transforming the scaffold-scaffold bond network. Whereas low-valency clients that compete for scaffoldscaffold binding sites decrease connectivity and stability, those that bind to alternate scaffold sites not required for LLPS or that have higher-than-scaffold valencies form additional scaffoldclient-scaffold bridges increasing stability. Proteins that establish more connections (via increased valencies, promiscuous binding, and topologies that enable multivalent interactions) support the stability of and are enriched within multicomponent condensates. Importantly, proteins that increase the connectivity of multicomponent condensates have higher critical points as pure systems or, if pure LLPS is unfeasible, as binary scaffold-client mixtures. Hence, critical points of accessible systems (i.e., with just a few components) might serve as a unified thermodynamic parameter to predict the composition of multicomponent condensates.