RNA modulates FUS condensate assembly, dynamics, and aggregation through diverse molecular contacts

Area of Science:

• Biochemistry
• Molecular Biology
• Biophysics

Background:

• Fused in sarcoma (FUS) protein forms ribonucleoprotein (RNP) granules via phase separation.
• Understanding protein-RNA interactions in these condensates is crucial but limited.

Purpose of the Study:

• To investigate how RNA modulates FUS phase separation and condensate properties.
• To elucidate the molecular mechanisms of FUS-RNA interactions within condensates.

Main Methods:

• Biochemical assays
• NMR spectroscopy
• Molecular dynamics simulations

Main Results:

• RNA concentration-dependently modulates FUS phase separation, enhancing it at low concentrations and disrupting it at high concentrations.
• RNA incorporation reduces condensate density, increases FUS mobility, and involves both LC and RGG1 domains.
• RNA accelerates the liquid-to-solid transition of FUS condensates, leading to fibrillar aggregate formation.

Conclusions:

• RNA plays a critical role in regulating FUS condensate assembly, dynamics, and maturation.
• Specific amino acid-RNA interactions, like glutamine-RNA contacts, stabilize FUS-RNA co-condensates.