Department of Biomedical Engineering, Center for Science & Engineering of Living Systems, Washington University in St. Louis, St. Louis, MO 63130, USA.
Department of Biochemistry and Pharmacology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
Mol Cell. 2022 Sep 1;82(17):3193-3208.e8. doi: 10.1016/j.molcel.2022.06.024. Epub 2022 Jul 18.
Aberrant phase separation of globular proteins is associated with many diseases. Here, we use a model protein system to understand how the unfolded states of globular proteins drive phase separation and the formation of unfolded protein deposits (UPODs). We find that for UPODs to form, the concentrations of unfolded molecules must be above a threshold value. Additionally, unfolded molecules must possess appropriate sequence grammars to drive phase separation. While UPODs recruit molecular chaperones, their compositional profiles are also influenced by synergistic physicochemical interactions governed by the sequence grammars of unfolded proteins and cellular proteins. Overall, the driving forces for phase separation and the compositional profiles of UPODs are governed by the sequence grammars of unfolded proteins. Our studies highlight the need for uncovering the sequence grammars of unfolded proteins that drive UPOD formation and cause gain-of-function interactions whereby proteins are aberrantly recruited into UPODs.
球状蛋白的异常相分离与许多疾病有关。在这里，我们使用模型蛋白体系来理解球状蛋白的去折叠状态如何驱动相分离和形成未折叠蛋白沉积物（UPOD）。我们发现，要形成 UPOD，去折叠分子的浓度必须超过一个阈值。此外，去折叠分子必须具有适当的序列语法来驱动相分离。虽然 UPOD 会招募分子伴侣，但它们的组成谱也受到由去折叠蛋白和细胞蛋白的序列语法控制的协同物理化学相互作用的影响。总的来说，相分离的驱动力和 UPOD 的组成谱是由去折叠蛋白的序列语法决定的。我们的研究强调了需要揭示驱动 UPOD 形成和导致功能获得性相互作用的去折叠蛋白的序列语法，这种相互作用导致蛋白质异常地被招募到 UPOD 中。
