Journal
MOLECULAR CELL
Volume 77, Issue 1, Pages 82-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2019.09.022
Keywords
-
Categories
Funding
- Catalyst Research Award from Johns Hopkins University
- Johns Hopkins University
- National Institute of Neurodegeneration and Stroke, National Alzheimer's Project Act (NAPA) [1-RF1-NS113636-01]
- National Science Foundation Physics Frontiers Center Program through the Center for the Physics of Living Cells [0822613, 1F31GM134641-01, 5T32GM007231-45]
- EMF/AFAR fellowship
- AARF fellowship
- Target ALS Springboard Fellowship
- NIH [R21NS090205, T32GM008275]
- G. Harold and Leila Y. Mathers Charitable Foundation
- Target ALS
- ALSA
- Packard Center for ALS Research
Ask authors/readers for more resources
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-beta 2 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available