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Abstract
Liquid-liquid phase separation (LLPS) of proteins that leads to formation of membrane-less organelles is critical to many biochemical processes in the cell. However, dysregulated LLPS can also facilitate aberrant phase transitions and lead to protein aggregation and disease. Accordingly, there is great interest in identifying small molecules that modulate LLPS. Here, we demonstrate that 4,4’-dianilino-1,1’-binaphthyl-5,5’-disulfonic acid (bis-ANS) and similar compounds are potent biphasic modulators of protein LLPS. Depending on context, bis-ANS can both induce LLPS de novo as well as prevent formation of homotypic liquid droplets. Our study also reveals the mechanisms by which bis-ANS and related compounds modulate LLPS and identify key chemical features of small molecules required for this activity. These findings may provide a foundation for the rational design of small molecule modulators of LLPS with therapeutic value.
Dysregulated liquid-liquid phase separation (LLPS) of proteins can facilitate aberrant phase transitions and lead to protein aggregation and disease. Here, authors demonstrate that 4,4’-dianilino-1,1’-binaphthyl-5,5’-disulfonic acid (bis-ANS) and similar compounds are potent biphasic modulators of protein LLPS.
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1 Case Western Reserve University, Department of Physiology and Biophysics, Cleveland, USA (GRID:grid.67105.35) (ISNI:0000 0001 2164 3847)
2 Case Western Reserve University, Center for RNA Science & Therapeutics, Cleveland, USA (GRID:grid.67105.35) (ISNI:0000 0001 2164 3847)
3 Case Western Reserve University, Center for RNA Science & Therapeutics, Cleveland, USA (GRID:grid.67105.35) (ISNI:0000 0001 2164 3847); Johns Hopkins School of Medicine, Department of Molecular Biology and Genetics, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311)