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

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Liquid-liquid phase separation (LLPS) is crucial for forming membraneless organelles.
• LLPS is increasingly linked to protein aggregation in neurodegenerative diseases like Alzheimer's.
• The U1-70K protein, found aggregated in Alzheimer's brains, is a potential therapeutic target.

Purpose of the Study:

• To investigate the LLPS mechanism of U1-70K protein fragments.
• To understand how LLPS contributes to protein aggregation in neurodegenerative conditions.
• To explore U1-70K as a potential target for Alzheimer's disease therapy.

Main Methods:

• Analysis of low-complexity (LC) domain fragments of U1-70K.
• In vitro studies to assess nucleotide-independent phase separation.
• In vivo experiments to confirm LLPS and aggregation.

Main Results:

• Two U1-70K LC domain fragments were found to undergo LLPS.
• Repetitive basic-acidic motifs in these fragments induce LLPS and aggregation.
• LLPS and aggregation were confirmed to occur in vivo.
• Ampholytic motif content dictates the transition between droplet formation and aggregation.

Conclusions:

• U1-70K fragments drive LLPS and aggregation through specific motifs.
• Protein domain composition influences the formation of diverse protein assemblies.
• Findings provide mechanistic insights into LLPS and aggregation in neurodegenerative diseases.