RNA Seeds Higher-Order Assembly of FUS Protein

•FUS binds multiple RNAs with extraordinary cooperativity•RNA nucleates the formation of fibrous FUS assemblies•FUS assemblies bind the CTD of RNA polymerase II•Aggregation of FUS protein in neurodegeneration may reflect its normal function

SummaryThe abundant nuclear RNA binding protein FUS binds the C-terminal domain (CTD) of RNA polymerase II in an RNA-dependent manner, affecting Ser2 phosphorylation and transcription. Here, we examine the mechanism of this process and find that RNA binding nucleates the formation of higher-order FUS ribonucleoprotein assemblies that bind the CTD. Both the low-complexity domain and the arginine-glycine rich domain of FUS contribute to assembly. The assemblies appear fibrous by electron microscopy and have characteristics of β zipper structures. These results support the emerging view that the pathologic protein aggregation seen in neurodegenerative diseases such as amyotrophic lateral sclerosis may occur via the exaggeration of functionally important assemblies of RNA binding proteins.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slide