Abstract：
:FUS is a nuclear RNA-binding protein, and its cytoplasmic aggregation is a pathogenic signature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It remains unknown how the FUS-RNA interactions contribute to phase separation and whether its phase behavior is affected by ALS-linked mutations. Here we demonstrate that wild-type FUS binds single-stranded RNA stoichiometrically in a length-dependent manner and that multimers induce highly dynamic interactions with RNA, giving rise to small and fluid condensates. In contrast, mutations in arginine display a severely altered conformation, static binding to RNA, and formation of large condensates, signifying the role of arginine in driving proper RNA interaction. Glycine mutations undergo rapid loss of fluidity, emphasizing the role of glycine in promoting fluidity. Strikingly, the nuclear import receptor Karyopherin-β2 reverses the mutant defects and recovers the wild-type FUS behavior. We reveal two distinct mechanisms underpinning potentially disparate pathogenic pathways of ALS-linked FUS mutants.
journal_name
Mol Celljournal_title
Molecular cellauthors
Niaki AG,Sarkar J,Cai X,Rhine K,Vidaurre V,Guy B,Hurst M,Lee JC,Koh HR,Guo L,Fare CM,Shorter J,Myong Sdoi
10.1016/j.molcel.2019.09.022subject
Has Abstractpub_date
2020-01-02 00:00:00pages
82-94.e4issue
1eissn
1097-2765issn
1097-4164pii
S1097-2765(19)30727-0journal_volume
77pub_type
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