Mechanism of Reentrant Liquid Condensation in Arginine-rich Low Complexity Domains

Arginine-rich (R-rich) low complexity domains (LCDs) are ubiquitous in eukaryotic RNA binding proteome, act as multi-valent RNA/protein-binding elements for liquid-liquid phase separation, and implicated in c9orf72-related ALS disease etiology. Recently, we showed that RNA mediates a remarkable reentrant liquid condensation of R-rich LCDs¹, a phenomenon that is also observed in the cell². Combining biophysical experiments and polymer physics theories, here we study the mechanism of the reentrant phase behavior of R-rich LCDs in ALS-associated protein FUS. We show that charge regulated electrostatic forces (long range) control condensation and de-condensation thresholds, whereas short-range attractions determine the stability of the condensates. Importantly, conditions promoting homotypic LCD-LCD and/or RNA-RNA interactions result in a more complex phase behavior, such as the formation of distinctive condensates with orthogonal physical properties. Together, our experiments and free-energy surface modeling suggest a highly tunable phase behavior of R-rich LCDs.

1. Banerjee, P. R. et al. 2017. Angew Chem Int Ed Engl. 56(38):11354.
2. Maharana, S. et al. 2018. Science. 360(6391):918.