Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge, CB3 0AS, UK.
Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge, CB3 0AS, UK.
Curr Opin Struct Biol. 2019 Oct;58:115-123. doi: 10.1016/j.sbi.2019.06.001. Epub 2019 Jul 10.
The role of water in protein function and aggregation is highly important and may hold some answers to understanding initiation of misfolding diseases such as Parkinson's, Alzheimer's and Huntington's where soluble intrinsically disordered proteins (IDPs) aggregate into fibrillar structures. IDPs are highly dynamic and have larger solvent exposed areas compared to globular proteins, meaning they make and break hydrogen bonds with the surrounding water more frequently. The mobility of water can be altered by presence of ions, sugars, osmolytes, proteins and membranes which differ in different cell types, cell compartments and also as cells age. A reduction in water mobility and thus protein mobility enhances the probability that IDPs can associate to form intermolecular bonds and propagate into aggregates. This poses an interesting question as to whether localised water mobility inside cells can influence the propensity of an IDP to aggregate and furthermore whether it can influence fibril polymorphism and disease outcome.
水在蛋白质功能和聚集中的作用非常重要，它可能为理解帕金森病、阿尔茨海默病和亨廷顿病等疾病的发病机制提供一些答案，在这些疾病中，可溶性无规卷曲蛋白质（IDP）会聚集形成纤维状结构。IDP 具有高度的动态性，与球状蛋白质相比，其溶剂暴露面积更大，这意味着它们与周围水形成和断裂氢键的频率更高。离子、糖、渗透调节剂、蛋白质和膜的存在会改变水的流动性，而这些物质在不同的细胞类型、细胞区室以及细胞衰老过程中是不同的。水流动性的降低，也就是蛋白质流动性的降低，会增加 IDP 形成分子间键并进一步聚集形成聚集体的可能性。这就提出了一个有趣的问题，即细胞内局部水流动性是否会影响 IDP 聚集的倾向，以及它是否会影响纤维状多态性和疾病结果。
