Stoichiometric versus stochastic interaction in models of liquid-liquid phase separation.
Stoichiometric versus stochastic interaction in models of liquid-liquid phase separation.
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液-液相分离模型中的化学计量与随机相互作用。
DOI：
10.1016/j.bpj.2021.12.008
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发表时间：
2022
影响因子：
3.4
通讯作者：
Ghosh,Kingshuk
中科院分区：
文献类型：
--
作者：
Ghosh,Kingshuk
在适当的温度和浓度条件下，荷电均聚物溶液可以分成两个不同的相：聚合物稀相(富含溶剂)和聚合物稠密相(1，2)。这种现象被称为液-液相分离(LLP)，在异聚蛋白质溶液中也很普遍。折叠蛋白的LLP已经众所周知几十年了(3，4)。相比之下，新发现的一类不能折叠成独特的“天然”结构的蛋白质、固有无序蛋白质(IDPs)或具有固有无序区域(IDR)的蛋白质的LLP只在过去十年才被报道。尽管是最近发现的，但由于其在许多生物过程中的关键作用，包括无膜细胞器的形成，对国内流离失所者和国内流离失所者的LLP越来越感兴趣(5)。在许多情况下，参与蛋白质中只存在低复杂性结构域就足以使溶液体系经历相分离。然而，在细胞内，相分离通常是多组分的，涉及不同的IDP或IDR序列，通常还有RNA。不同生物分子之间在无限稀释极限附近的络合作用，远离上述溶液行为，是决定生物功能的多组分现象的另一个例子。众所周知，两种类型的折叠蛋白质之间或一种无序和一种折叠蛋白质之间发生络合作用，最近有报道称，两种无序蛋白质也可以形成无序复合体(6)。两种相反电荷的合成聚合物之间的络合作用是众所周知的，也是材料科学应用中的一个活跃的话题(7，8)。两种类型的分子(A和B)之间络合的一个明显特征是坚持固定的化学计量比；例如，m个A和n个B分子可以形成一个复杂的AmBn。鉴于络合和LLP在生物学中的优势，在溶液中(三组分包括溶剂)的双组分生物聚合物体系很可能同时发生络合和LLP(在较高浓度下)。我们如何在两个政权之间架起桥梁，并将两个不同的进程结合在一起？林、陈和他的同事通过结合数学建模和实验对这个问题进行了深入的讨论(9)。通过识别所有允许的交互的集合，可以认识到问题的丰富性和难度。双组分(A和B)生物聚合物体系的LLP通常受同型(A±A，B±B)和异型(A±B)相互作用的驱动，此外还有聚合物-溶剂相互作用。当A和B都是IDPs或IDR时，相互作用通常是不稳定的或“随机的”，主要是由于大量的无序和构象波动。然而，如果A和B形成络合物，就会产生一个额外的成分(络合分子，即AmBn)。络合物通常会失去大量的构象熵，从而限制了在两个络合物之间形成“随机”相互作用的能力。因此，复合体可能会以更“特定”的方式相互作用。这两种类型的交互--特定交互和随机交互--如何决定有限合伙人？化学计量复合体是否首先形成，然后以特定的方式相互作用以驱动有限合伙人？或者有限责任合伙人的过程同时涉及“特定的”和“非特定的或随机的”相互作用？通过研究两种蛋白质Syn-Gap和PSD-95的模型系统回答了这些基本问题，该复合体具有3：2的化学计量比，并作为突触后密度(PSD)的最简单模型。之前的…
Under appropriate temperature and concentration conditions, chargeneutral homopolymer solutions can segregate into two distinct phases: a polymer-dilute (solvent-rich) and a polymer-dense phase (1, 2). This phenomenon, known as liquid-liquid phase separation (LLPS), is widespread in hetero-polymeric protein solutions as well. The LLPS of folded proteins has been well known for many decades (3, 4). In contrast, the LLPS of newly found classes of proteins that do not fold into unique ‘‘native’’structures, intrinsically disordered proteins (IDPs) or proteins with intrinsically disordered regions (IDRs), has been reported only in the last decade. Although recently discovered, there is growing interest in LLPS of IDPs and IDRs due to their critical role in a multitude of biological processes including the formation of membraneless organelles (5). In many instances, the presence of only lowcomplexity domains in the participating proteins is sufficient for the solution system to undergo phase separation. However, inside a cell, phase separation is often multicomponent, involving different IDP or IDR sequences and often RNA as well. Complexation between different biomolecules near the infinitely dilute limit, far from the solution behavior described above, is another example of multicomponent phenomena that dictate biological function. Complexation is well known to take place between two types of folded proteins or between a disordered and a folded protein, and it has been recently reported that two types of disordered proteins can also form a disordered complex (6). Complexation between two oppositely charged synthetic polymers is well known and a topic of active interest in materials science applications (7, 8) as well. A defining feature of complexation between two types (A and B) of molecules is adherence to a fixed stoichiometry; for example, m number of A and n number of B molecules can form a complex AmBn. Given the preponderance of complexation and LLPS in biology, it is likely that a two-component biopolymer system in solution (three component including the solvent) can undergo both complexation and LLPS (at higher concentration). How do we bridge the two regimes and couple the two different processes? Lin, Chan, and colleagues provide a deeply insightful discussion of this problem by combining mathematical modeling and experiments (9). The richness and the difficulty of the problem can be appreciated by recognizing the sets of all allowed interactions. The LLPS of a two-component (A and B) biopolymer system is typically driven by homotypic (A À A, B À B) and heterotypic (A À B) interactions, in addition to polymer-solvent interactions. When A and B are both IDPs or IDRs, the interactions are typically labile or ‘‘stochastic,’’primarily due to substantial disorder and conformational fluctuations. However, if A and B form complexes, an additional component (complexed molecules, ie, AmBn) arises. Complexes are typically expected to lose substantial conformational entropy, limiting the ability to form ‘‘stochastic’’interactions between two complexes. Consequently, complexes may interact in a more ‘‘specific’’manner. How do these two types of interactions—specific versus stochastic—dictate LLPS? Do stoichiometric complexes form first and subsequently interact in a specific manner to drive LLPS? Or does the process of LLPS involve both ‘‘specific’’and ‘‘nonspecific or stochastic’’interactions?The article (9) by Lin et al. answers these fundamental questions by studying the model system of two proteins, Syn-Gap and PSD-95, that complex with a 3: 2 stoichiometry and serve as the simplest model of postsynaptic densities (PSD). Previous …