Kinase-phosphatase cycles drive self-sustained oscillations of protein condensates

Phase-separated protein condensates organize biochemical processes in cells. ATP-driven enzymatic reactions can change the physical properties and even trigger the dissolution of such condensates. Here we use molecular simulations to show how ATP-driven kinase and phosphatase reactions modulate the organization of TDP-43 low complexity domain (LCD) condensates. TDP-43 phosphorylation is enhanced by condensation, as CK1δ preferentially binds to and acts in TDP-43 LCD condensates, whereas dephosphorylation by the phosphatase calcineurin occurs predominantly in the dilute phase. This differential recruitment of kinases and phosphatases, together with the slow redistribution of kinases into newly formed condensates, triggers oscillatory appearance and disappearance of TDP-43 LCD condensates. The oscillations are self-sustained, persisting at constant chemical driving, showing that an antagonistic kinase-phosphatase pair can endow a condensate with autonomous dynamics rather than only setting its structure.