Department of Chemistry & Biochemistry, Kent State University, Kent, OH 44242, USA.
Department of Chemistry & Biochemistry, Advanced Materials and Liquid Crystal Institute, Department of Biomedical Sciences, Kent State University, Kent, OH 44242, USA.
Angew Chem Int Ed Engl. 2022 Jun 7;61(23):e202113156. doi: 10.1002/anie.202113156. Epub 2022 Apr 5.
In Tau protein condensates formed by the Liquid-Liquid Phase Separation (LLPS) process, liquid-to-solid transitions lead to the formation of fibrils implicated in Alzheimer's disease. Here, by tracking two contacting Tau-rich droplets using a simple and nonintrusive video microscopy, we found that the halftime of the liquid-to-solid transition in the Tau condensate is affected by the Hofmeister series according to the solvation energy of anions. After dissecting functional groups of physiologically relevant small molecules using a multivariate approach, we found that charged groups facilitate the liquid-to-solid transition in a manner similar to the Hofmeister effect, whereas hydrophobic alkyl chains and aromatic rings inhibit the transition. Our results not only elucidate the driving force of the liquid-to-solid transition in Tau condensates, but also provide guidelines to design small molecules to modulate this important transition for many biological functions for the first time.
在由液-液相分离（LLPS）过程形成的 Tau 蛋白凝聚物中，液-固转变导致了阿尔茨海默病中涉及的纤维的形成。在这里，通过使用简单且非侵入性的视频显微镜跟踪两个接触的富含 Tau 的液滴，我们发现 Tau 凝聚物中液-固转变的半衰期受离子的溶剂化能影响，根据霍夫迈斯特序列而变化。通过使用多元方法对生理相关小分子的官能团进行剖析，我们发现带电荷的基团以类似于霍夫迈斯特效应的方式促进液-固转变，而疏水性烷基链和芳环则抑制转变。我们的研究结果不仅阐明了 Tau 凝聚物中液-固转变的驱动力，而且还首次为设计小分子来调节这种重要转变以用于许多生物学功能提供了指导。
