Intrinsically disordered proteins in overcrowded milieu: Membrane-less organelles, phase separation, and intrinsic disorder

Although the cellular interior is crowded with various biological macromolecules, the distribution of these macromolecules is highly inhomogeneous. Eukaryotic cells contain numerous proteinaceous membrane-less organelles (PMLOs), which are condensed liquid droplets formed as a result of the reversible and highly controlled liquid-liquid phase transitions. The interior of these cellular bodies represents an overcrowded milieu, since their protein concentrations are noticeably higher than those of the crowded cytoplasm and nucleoplasm. PMLOs are different in size, shape, and composition, and almost invariantly contain intrinsically disordered proteins (e.g., eIF4B and TDP43 in stress granules, TTP in P-bodies, RDE-12 in nuage, RNG105 in RNA granules, centrins in centrosomes, NOPP140 in nucleoli, SRSF4 in nuclear speckles, Saf-B in nuclear stress bodies, NOLC1 in Cajal bodies, CBP in PML nuclear bodies, SOX9 in paraspeckles, KSRP in perinucleolar compartment, and hnRNPG and Sam68 in Sam68 nuclear body, to name a few), which indicates that the formation of these phase-separated droplets is crucially dependent on intrinsic disorder. The goal of this review is to show the roles of intrinsic disorder in the magic behind biological liquid-liquid phase transitions that lead to the formation of PMLOs.