The intrinsically disordered region from PP2C phosphatases functions as a conserved CO 2 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 CO 2 concentrations is critical for all organisms. Conversion of CO 2 to HCO 3 - by carbonic anhydrase and subsequent HCO 3 - -triggered signalling are thought to be important for cellular responses to CO 2 (refs. 1-3 ). However, carbonic anhydrases are suggested to transduce a change in CO 2 rather than be a direct CO 2 sensor 4,5 , the mechanism(s) by which organisms sense CO 2 remain unknown. Here we demonstrate that a unique group of PP2C phosphatases from fungi and plants senses CO 2 , but not HCO 3 - , 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 CO 2 in an IDR-dependent manner. The IDRs in PP2Cs are characterized by a sequence of polar amino acids enriched in serine/threonine, which provides CO 2 responsiveness. CO 2 -responsive activation of PP2Cs via the serine/threonine-rich IDR-mediated phase separation represents a direct CO 2 sensing mechanism and is widely exploited.