期刊
SCIENCE ADVANCES
卷 5, 期 11, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aax5349
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资金
- National Natural Science Foundation of China [91853116, 21672019]
- National Key Research and Development Program [2017YFF0205402]
- Fundamental Research Funds for the Central Universities [XK1802-8]
- Research projects on biomedical transformation of China-Japan Friendship Hospital [PYBZ1812, PYBZ1815]
Liquid-liquid phase separation (LLPS) facilitates the formation of functional membraneless organelles and recent reports have linked this phenomenon to protein aggregation in neurodegenerative diseases. Understanding the mechanism of LLPS and its regulation thus promises to shed light on the pathogenesis of these conditions. The RNA-binding protein U1-70K, which aggregates in brains of Alzheimer's disease patients, is considered a potential target for Alzheimer's therapy. Here, we report that two fragments in the low-complexity (LC) domain of U1-70K can undergo LLPS. We have demonstrated that the repetitive basic-acidic motifs in these fragments induce nucleotide-independent phase separation and initiate aggregation in vitro. We also have confirmed that LLPS and aggregation occur in vivo and that the content of ampholytic motifs in a protein domain determines the transition between droplets and aggregation, providing insights into the mechanism underlying the formation of diverse assembly states.
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