Figure 3.

Dephosphorylation of P4-ATPases and Na⁺/K⁺-ATPase is activated by binding of the transported substrate. (A) Experimental data (Coleman et al., 2012) showing the accelerating effect of addition of phosphatidylserine (PS) on dephosphorylation of ATP8A2 (open circles). No dephosphorylation occurs when phosphatidylcholine (PC) is added (open triangles). The PS-induced dephosphorylation is blocked by the E198Q mutation replacing the glutamate in the DGET motif of the A domain with glutamine (filled triangles). (B) Reaction cycle of P4-ATPases proposed on the basis of the finding illustrated in A together with additional analysis of the conformations of the phosphoenzyme intermediate of ATP8A2 (Coleman et al., 2012). (C) Classic Post-Albers model for the reaction cycle of Na⁺,K⁺-ATPase (Post et al., 1972) illustrating that the activation of dephosphorylation of the P4-ATPase by PS (coming from the exoplasmic lipid bilayer leaflet) shown in (A,B) is analogous to the activation of dephosphorylation of Na⁺,K⁺-ATPase by K⁺ (coming from the exoplasmic medium). Na⁺ binding from the cytoplasm is required for phosphorylation of Na⁺,K⁺-ATPase, whereas no known ion or other substrate needs to bind to the P4-ATPase to allow phosphorylation (see text for more explanation).