Percolation physics and density transition frameworks converge in biomolecular condensation.
Percolation physics and density transition frameworks converge in biomolecular condensation.
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DOI：
10.1073/pnas.2210177119
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发表时间：
2022-08-09
影响因子：
11.1
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中科院分区：
文献类型：
--
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近年来迅速增长的工作使我们对生物分子凝聚物(或更广泛地说，各种形式的中尺度到宏观生物物质)及其在生物学和疾病中的转变的重要性的理解取得了令人兴奋的进展(1-3)。乍一看，液体如何通过多孔/颗粒材料渗透的物理学或网络连接中的相关概念似乎与进一步加深我们对生物分子凝聚物的机械理解无关。然而，有趣的是，渗流理论已经被广泛应用于聚合物物理(4，5)和相变(以及许多其他领域)的相关领域。现在，在一个令人兴奋的进展中，Kar等人(6)描述了实验、概念和计算工作的组合，探索了渗流物理和一类与神经退行性疾病有关的重要生物分子缩合之间的联系。生物分子凝析油领域的概念性理解一直广泛地受到简单成核形式和Flory-Huggins类型理论的指导。这类理论的预测是，在单一大分子(如蛋白质)在溶剂中的饱和浓度(Csat)以下，该大分子将主要以单体和非常小的团簇的形式存在，因为形成团簇的能量依赖于大小。只有在饱和浓度以上，才会发生相分离(密度转变)，从而形成致密相(也称为微米级液滴)。现在，Kar等人(6)描述了一组广泛的数据，可以提供对这一预测的测试。这项工作中研究的蛋白质是FET(FUS，EWSR1，TAF15)家族蛋白质，与神经退行性疾病有关，已在该领域进行了广泛的研究。利用成像、动态光散射(DLS)和单颗粒(跟踪、多参数荧光和微流体)实验的组合，Kar等人(6)表明，虽然在低于有效csat的溶液中没有观察到相分离，但这些蛋白质的亚饱和溶液包含一系列纳米尺度的团簇。数据表明，团簇服从重尾分布，较大的中尺度团簇丰度较低，分布随总蛋白浓度变化而变化。只有在csat以上，才会出现更大的微米大小的天体，显示出粗化。荧光共振能量转移/DLS数据表明，团簇的形成是可逆的，蛋白质在簇间交换。总之，这些数据与上面讨论的基于成核理论的预测形成了鲜明的对比。然后，作者继续援引基于渗流理论的观点，在他们和其他先前工作的基础上，为这些观察结果提供解释(4，5，7，8)。
A rapidly growing body of work in recent years has resulted in exciting advances in our understanding of the importance of biomolecular condensates (or, more generally, various forms of mesoscale to macroscale biological matter) and their transitions in biology and disease (1–3). At first glance, the physics of how liquids percolate through porous/granular materials or related concepts in network connectivity may not seem relevant to furthering our mechanistic understanding of biomolecular condensates. Interestingly, however, percolation theory has been extensively used in the related areas of polymer physics (4, 5) and phase transitions (as well as in numerous other fields). Now, in an exciting advance, Kar et al.(6) describe a combination of experimental, conceptual, and computational work that explores the connection between percolation physics and an important class of biomolecular condensation with links to neurodegenerative diseases. Conceptual understanding in the biomolecular condensate field has been extensively guided by simple forms of nucleation and Flory–Huggins-type theories. A prediction of this type of theory is that, below a saturation concentration (csat) of a single macromolecule (eg, protein) in a solvent, the macromolecule will exist mainly as monomers and very small clusters, because there is a size-dependent energy penalty for cluster formation. It is only above the saturation concentration that phase separation (a density transition) will occur, resulting in the formation of a dense phase (aka micrometer-sized droplets). Now, Kar et al.(6) describe a broad set of data that can provide a test of this prediction.The proteins studied in this work are FET (FUS, EWSR1, TAF15) family proteins, with links to neurodegenerative disease, which have been extensively investigated in the field. Using a combination of imaging, dynamic light scattering (DLS), and single-particle (tracking, multiparameter fluorescence, and microfluidics-based) experiments, Kar et al.(6) show that, while phase separation is not observed in solutions below an effective csat, subsaturated solutions of these proteins contain a range of nanoscale clusters. The data indicate that clusters follow a heavytailed distribution, with low abundance of larger mesoscale clusters and distributions changing with total protein concentration. It is only above csat that larger micrometer-sized bodies that display coarsening appear. Fluorescence resonance energy transfer/DLS data show that cluster formation is reversible, and that protein exchanges between clusters. Together, these data draw a sharp contrast with the predictions based on nucleation theory discussed above. The authors then go on to invoke percolation theory–based ideas to offer an explanation for these observations, building on their and other previous work (4, 5, 7, 8).
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