Interplay of the folded domain and disordered low-complexity domains along with RNA sequence mediate efficient binding of FUS with RNA

RNA binding ability of Fused in Sarcoma (FUS) protein is crucial to its cellular function. Our molecular simulation study on FUS-RNA complex provides atomic resolution insights into the observations from biochemical studies and also illuminate our understanding of molecular driving forces that mediate the structure, stability, and interaction of RRM and RGG domains of FUS with a stem-loop junction RNA. We observe a clear cooperativity and division of labour among the ordered (RRM) and disordered domains (RGG1 and RGG2 domain) of FUS that leads to an organized and tighter RNA binding. Irrespective of the length of RGG2, the RGG2-RNA interaction is confined to the stem-loop junction and the proximal stem regions. On the other hand, the RGG1-RNA interactions are primarily with the longer RNA stem. We find that the C-terminus of RRM, which make up the “boundary residues” that connect the folded RRM with the long disordered RGG2 stretch of the protein, plays a critical role in RNA binding with the RRM domain. Our study provides high-resolution molecular insights into the FUS-RNA interactions and forms the basis for understanding the molecular origins of full-length FUS interaction with RNA.