Liquid–liquid phase separation of tau protein: The crucial role of electrostatic interactions

Recent studies have indicated that tau, a protein involved in Alzheimer's disease and other neurodegenerative disorders, has a propensity to undergo liquid–liquid phase separation (LLPS). However, the mechanism of this process remains unknown. Here, we demonstrate that tau LLPS is largely driven by intermolecular electrostatic interactions between the negatively charged N-terminal and positively charged middle/C-terminal regions, whereas hydrophobic interactions play a surprisingly small role. Furthermore, our results reveal that, in contrast to previous suggestions, phosphorylation is not required for tau LLPS. These findings provide a foundation for understanding the mechanism by which phosphorylation and other posttranslational modifications could modulate tau LLPS in the context of specific physiological functions as well as pathological interactions.