2024 AIChE Annual Meeting
(203e) Deciphering the Molecular Details of Fus LC-RGG1 Phase Separation with RNA
Fused in Sarcoma (FUS), an RNA-binding protein, plays a crucial role in various RNA metabolic processes through phase separation with RNA molecules. FUS comprises an N-terminal low-complexity (LC) domain that mediates phase separation and a C-terminal RNA-binding domain (RBD). The folded RNA recognition motif (RRM) and zinc finger (ZnF) domains within RBD bind RNA with specific sequence and structural preferences, while the three disordered arginine-rich regions (RGGs) bind RNA nonspecifically. While information about specific interaction between folded domains and RNA are available, it is still not understood how disordered domains interact with RNA. In this study, we employed multiscale molecular simulations to investigate whether FUS LC-RGG1 undergoes phase separation with RNA and what is the driving force behind it. The findings suggest that both the LC and RGG1 domains synergistically interact with RNA to undergo phase separation, with RGG1 interacting more with RNA as compared to LC domain. Moreover, the results indicate that along with arginine, which is known to have higher propensity to interact with RNA, a diverse network of interactions involving tyrosine, and polar residues with RNA also drives the co-phase separation. Overall, this study, combined with NMR spectroscopy data, provides a comprehensive understanding of how the phase separation of FUS's disordered domains is facilitated by its nonspecific interactions with RNA, highlighting the potential interplay between FUS and RNA in cellular processes.