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PMID: 31723601 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Low-complexity domain of U1-70K modulates phase separation and aggregation through distinctive basic-acidic motifs.

Science advances ·Vol. 5 ·No. 11 ·2019-00-00 ·Pages eaax5349

Xue S, Gong R, He F, Li Y, Wang Y, Tan T, Luo SZ

Abstract

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.

MeSH Terms
Alzheimer Disease/genetics,metabolism Amino Acid Motifs Amino Acid Sequence Brain/metabolism,pathology Humans Hydrogen-Ion Concentration Liquid-Liquid Extraction Microscopy, Confocal Peptide Fragments/chemistry,genetics,metabolism Phase Transition Protein Aggregation, Pathological Protein Domains Ribonucleoprotein, U1 Small Nuclear/chemistry,genetics,metabolism Sequence Homology, Amino Acid
Chemicals
Peptide Fragments Ribonucleoprotein, U1 Small Nuclear SNRNP70 protein, human
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Xue Song ORCID
Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
Gong Rui
Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
He Fanqi
Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
Li Yanqin
Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
Wang Yunjia
Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
Tan Tianwei
Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
Luo Shi-Zhong ORCID
Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
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Article Info
Journal
Science advances
Abbr.
Sci Adv
ISSN
2375-2548
DOI
10.1126/sciadv.aax5349
Published
2019-00-00
Epub
2019-00-06
Pages
eaax5349
Language
English
Region
United States
NLM ID
101653440
PMCID
PMC6834393
Subset
IM
External Links
PubMed source DOI: 10.1126/sciadv.aax5349 PMC Full Text View journal details
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