The intrinsically disordered region from PP2C phosphatases functions as a conserved CO₂ sensor

Carbon dioxide not only plays a central role in the carbon cycle, but also acts as a crucial signal in living cells. Adaptation to changing CO₂ concentrations is critical for all organisms. Conversion of CO₂ to HCO₃^- by carbonic anhydrase and subsequent HCO₃^--triggered signalling are thought to be important for cellular responses to CO₂ (refs. ^1-3). However, carbonic anhydrases are suggested to transduce a change in CO₂ rather than be a direct CO₂ sensor^4,5, the mechanism(s) by which organisms sense CO₂ remain unknown. Here we demonstrate that a unique group of PP2C phosphatases from fungi and plants senses CO₂, but not HCO₃^-, to control diverse cellular programmes. Different from other phosphatases, these PP2Cs all have an intrinsically disordered region (IDR). They formed reversible liquid-like droplets through phase separation both in cells and in vitro, and were activated in response to elevated environmental CO₂ in an IDR-dependent manner. The IDRs in PP2Cs are characterized by a sequence of polar amino acids enriched in serine/threonine, which provides CO₂ responsiveness. CO₂-responsive activation of PP2Cs via the serine/threonine-rich IDR-mediated phase separation represents a direct CO₂ sensing mechanism and is widely exploited.