한빛사 논문
Amirhossein Ghanbari Niaki1,9, Jaya Sarkar1,9, Xinyi Cai1, Kevin Rhine2, Velinda Vidaurre2, Brian Guy2, Miranda Hurst1, Jong Chan Lee3, Hye Ran Koh1,4, Lin Guo5,6, Charlotte M. Fare6,7, James Shorter6,7, Sua Myong1,8,10,*
1 T.C. Jenkins Department of Biophysics, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA
2 Cellular Molecular Developmental Biology and Biophysics, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA
3 Department of Biophysics and Biophysical Chemistry and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205, USA
4 Department of Chemistry, Chung-Ang University, Seoul 054974, Korea
5 Department of Biochemistry and Molecular Biology, Jefferson University, Philadelphia, PA 19107, USA
6 Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
7 Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
8 Department of Physics, Center for the Physics of Living Cells and Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
9These authors contributed equally
10Lead Contact
*Corresponding author : Sua Myong
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.
Keywords : FUS mutation; ALS/FTD; liquid liquid phase separation; dynamic; RNA interaction; single molecule FRET; aberrant condensation; fluidity; Karyopherin-β2
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