MOLECULAR MECHANISMS OF ATP-MODULATED LIQUID-LIQUID PHASE SEPARATION (LLPS) OF TDP-43 AND SARS-COV-2 NUCLEOCAPSID PROTEIN

An estimated 40% of human proteome has undergone LLPS; delineating its molecular mechanisms may reveal principles undiscovered in physiology and open avenues for pathology. All living cells inexplicably maintain 2-14 mM ATP. Strikingly, in 2017, ATP (> 5 mM) was demonstrated to behave as a biohydrotrope to prevent protein LLPS. However, a high-resolution mechanism for ATP-modulated LLPS has been lacking so far. Here we included TDP-43 and SARS-CoV-2 N proteins as two paradigms to decipher how ATP regulates protein LLPS. The results revealed that ATP biphasically modulates the TDP-43 PLD and N protein LLPS by interacting with Arg/Lys and that ATP-modulated LLPS might be conserved from human to virus. These findings advance knowledge of ATP repertoire in fine-tuning LLPS and suggest ATP may be a crucial factor hijacked by SARS-CoV-2 to steer its life cycle. We, therefore, recommended ATP as a lead for designing drugs against neurodegeneration and viral infections.

Author dc:creator

• DANG MEI

• Liquid-liquid phase separation (LLPS), ATP, nucleic acids, TDP-43 PLD, SARS-CoV-2 Nucleocapsid (N) protein, NMR spectroscopy