RNA Seeds Higher-Order Assembly of FUS Protein

• Published in: Cell reports (Cambridge) Vol. 5; no. 4; pp. 918 - 925
• Main Authors: Schwartz, Jacob C., Wang, Xueyin, Podell, Elaine R., Cech, Thomas R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.11.2013; Elsevier
• Subjects: Amyotrophic Lateral Sclerosis - genetics; Cell Line; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA Methyltransferase 3B; HEK293 Cells; Humans; Promoter Regions, Genetic; Protein Binding; Protein Structure, Tertiary; Ribonucleoproteins - biosynthesis; Ribonucleoproteins - genetics; Ribonucleoproteins - metabolism; RNA - genetics; RNA Polymerase II - metabolism; RNA-Binding Protein FUS - biosynthesis; RNA-Binding Protein FUS - genetics; RNA-Binding Protein FUS - metabolism; Transcription, Genetic
• DOI: 10.1016/j.celrep.2013.11.017
• ISSN: 2211-1247

The 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. [Display omitted] •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 Cech and colleagues show that RNA nucleates the formation of higher-order FUS ribonucleoprotein assemblies that bind the C-terminal domain. 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 by the exaggeration of functionally important assemblies of RNA binding proteins.