Small Molecules Modulate Liquid‐to‐Solid Transitions in Phase‐Separated Tau Condensates. (5th April 2022)

• Record Type: Journal Article
• Authors: Jonchhe, Sagun; Pan, Wei; Pokhrel, Pravin; Mao, Hanbin
• Is Part Of: Angewandte Chemie. Volume 134:Number 23(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-04-05
• Subjects: Hofmeister Effect -- Liquid–Liquid Phase Separation -- Liquid-to-Solid Transition -- Small-Molecule Modulation -- Tau Condensates; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.202113156
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: 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. Abstract : Small molecules with hydrophobic groups (yellow tetrahedral sticks) interact with Tau proteins (red), stabilizing Liquid–Liquid Phase Separation (LLPS) condensates in the liquid‐like phase. Tau proteins start to interact with neighboring Tau molecules and aggregate into the solid‐like state in the droplet. Salting out ions following the Hofmeister series facilitate the liquid‐to‐solid transition.