Protein Phase Separation Arising from Intrinsic Disorder: First-Principles to Bespoke Applications
Protein Phase Separation Arising from Intrinsic Disorder: First-Principles to Bespoke Applications
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由内在无序引起的蛋白质相分离：定制应用的第一原理
DOI：
10.1021/acs.jpcb.1c01146
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Chilkoti, Ashutosh
中科院分区：
文献类型：
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作者：
Shapiro, Daniel Mark;Ney, Max;Eghtesadi, Seyed Ali;Chilkoti, Ashutosh
在过去的十年里，生物分子的相分离已经成为研究的热点，越来越多的研究表明这一现象涉及到几乎所有的生物功能，包括但不限于动态平衡、应激反应、基因调控、细胞分化和疾病。关于生物分子(NAT)液-液相分离(LLP)的基本物理基础，先前已经发表了出色的评论。Phys.2015，11,899-904)和LLP在生理和疾病中天然存在(科学2017,357，Eaaf4382；生物化学2018，57,2479-2487；化学。修订版2014、114、6844-6879)。在这里，我们回顾了LLP的理论物理基础如何被用来更好地理解自然系统中经历LLP的生物分子的行为，以及这种理解如何也导致了显示生物分子相分离的新型合成系统的发展，以及利用这些现象的技术。在这篇综述的第一部分中，我们探索了生物分子和合成大分子相分离背后的理论，并介绍了几个值得注意的相分离生物分子。在第二部分中，我们介绍了用于研究相分离蛋白质的实验和计算方法，以及这些技术如何揭示了生理和疾病中相分离的潜在机制。最后，在第三部分中，我们介绍了工程相分离多肽的开发和应用，从控制它们的自组装到创建定义的超分子结构，到使用显示LLP的工程IDPs重新编程生物过程。
The phase separation of biomolecules has become the focus of intense research in the past decade, with a growing body of research implicating this phenomenon in essentially all biological functions, including but not limited to homeostasis, stress responses, gene regulation, cell differentiation, and disease. Excellent reviews have been published previously on the underlying physical basis of liquid–liquid phase separation (LLPS) of biological molecules (Nat. Phys.2015,11, 899–904) and LLPS as it occurs natively in physiology and disease (Science2017,357, eaaf4382;Biochemistry2018,57, 2479–2487;Chem. Rev.2014,114, 6844–6879). Here, we review how the theoretical physical basis of LLPS has been used to better understand the behavior of biomolecules that undergo LLPS in natural systems and how this understanding has also led to the development of novel synthetic systems that exhibit biomolecular phase separation, and technologies that exploit these phenomena. In part 1 of this Review, we explore the theory behind the phase separation of biomolecules and synthetic macromolecules and introduce a few notable phase-separating biomolecules. In part 2, we cover experimental and computational methods used to study phase-separating proteins and how these techniques have uncovered the mechanisms underlying phase separation in physiology and disease. Finally, in part 3, we cover the development and applications of engineered phase-separating polypeptides, ranging from control of their self-assembly to create defined supramolecular architectures to reprogramming biological processes using engineered IDPs that exhibit LLPS.