Regulation of bacterial ATP synthase activity: A gear‐shifting or a pawl–ratchet mechanism?

The F1FO‐ATP synthase is a rotary reversible nanomotor that makes ATP. Upon blockage of the respiratory chain or when uncoupling agents are present, the enzyme is prone to hydrolyze ATP, but natural inhibitor proteins prevent this wasteful activity. Here, we address the inhibitory mechanism of the ε‐subunit of Escherichia coli and discuss whether it acts as a modulator of the ATPase turnover (gear‐shifting mechanism) or as an all‐or‐nothing inhibitor (pawl–ratchet mechanism). Comment on: https://doi.org/10.1111/febs.15616 The F1Fo‐ATP synthase, a widely distributed nanomotor responsible of ATP synthesis, rotates its central rotor reversibly: In the clockwise direction when viewed from the Fo (with the observer facing the positive side of the energy transducing membrane and looking down into the negative side of the membrane), it functions as ATP synthase, while in counterclockwise sense, it operates as a proton‐pumping ATP hydrolase. Regulation exerted by naturally occurring inhibitory proteins of the enzyme appears to function by avoiding ATP hydrolysis while preserving ATP synthesis. The work of Liu et al. describes an unbiased, elegant analytical pipeline that provides important insights into the inhibitory role of the ε‐subunit of the bacterial F1Fo‐ATP synthase in vivo. We discuss if a gear‐shifting versus a pawl–ratchet mechanism may explain the regulatory role of the ε‐subunit.