Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia.
Proc Natl Acad Sci U S A. 2020 Dec 29;117(52):33254-33262. doi: 10.1073/pnas.2007670117. Epub 2020 Dec 14.
A wide range of proteins have been reported to condensate into a dense liquid phase, forming a reversible droplet state. Failure in the control of the droplet state can lead to the formation of the more stable amyloid state, which is often disease-related. These observations prompt the question of how many proteins can undergo liquid-liquid phase separation. Here, in order to address this problem, we discuss the biophysical principles underlying the droplet state of proteins by analyzing current evidence for droplet-driver and droplet-client proteins. Based on the concept that the droplet state is stabilized by the large conformational entropy associated with nonspecific side-chain interactions, we develop the FuzDrop method to predict droplet-promoting regions and proteins, which can spontaneously phase separate. We use this approach to carry out a proteome-level study to rank proteins according to their propensity to form the droplet state, spontaneously or via partner interactions. Our results lead to the conclusion that the droplet state could be, at least transiently, accessible to most proteins under conditions found in the cellular environment.
大量的蛋白质已被报道能够凝聚成致密的液相，形成可逆的液滴状态。液滴状态控制的失败会导致更稳定的淀粉样状态的形成，这通常与疾病有关。这些观察结果促使人们思考有多少种蛋白质可以经历液-液相分离。在这里，为了解决这个问题，我们通过分析目前关于液滴驱动蛋白和液滴结合蛋白的证据，讨论了蛋白质液滴状态的物理原理。基于液滴状态是由与非特异性侧链相互作用相关的大构象熵稳定的概念，我们开发了 FuzDrop 方法来预测能够自发相分离的液滴促进区域和蛋白质。我们使用这种方法进行了一项蛋白质组水平的研究，根据蛋白质形成液滴状态的倾向对其进行排序，无论是自发的还是通过伴侣相互作用。我们的结果得出结论，在细胞环境中发现的条件下，液滴状态至少可以在瞬时情况下，对大多数蛋白质都是可及的。
