The stability of NPM1 oligomers regulated by acidic disordered regions controls the quality of liquid droplets.

The article focuses on the molecular regulation of nucleophosmin 1 (NPM1) oligomer stability and its impact on nucleolar liquid–liquid phase separation (LLPS). It demonstrates that acidic amino acids in the intrinsically disordered regions (IDRs) of NPM1, particularly in the N-terminal and central acidic stretches, attenuate oligomer stability by disrupting key monomer–monomer interactions within the oligomerization domain. Phosphorylation within these IDRs increases net negative charges, further destabilizing oligomers and enhancing the fluidity of NPM1-formed liquid droplets, which are essential for nucleolar assembly and dynamics. Molecular dynamics simulations and mutational analyses reveal that interactions involving residues Tyr67, His40, and His115 are critical for oligomer formation, and modulation of these interactions by acidic IDRs and phosphorylation regulates nucleolar phase behavior during the cell cycle.