Small molecules as potent biphasic modulators of protein liquid-liquid phase separation

W. Michael Babinchak, Benjamin K. Dumm, Sarah Venus, Solomiia Boyko, Andrea A. Putnam, Eckhard Jankowsky and Witold K. Surewicz ()
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W. Michael Babinchak: Case Western Reserve University
Benjamin K. Dumm: Case Western Reserve University
Sarah Venus: Case Western Reserve University
Solomiia Boyko: Case Western Reserve University
Andrea A. Putnam: Case Western Reserve University
Eckhard Jankowsky: Case Western Reserve University
Witold K. Surewicz: Case Western Reserve University

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19211-z

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