FIGURE 8.

Model of reaction cycle-dependent transporter-subunit rearrangements in P₂- and P_2C-ATPase complexes. A and B, schematics of the E₁ and E₂P forms of P₄ (A) and P_2C-ATPases (B) in complex with their accessory subunit (Cdc50 subunit for P₄-ATPases; β subunit for P_2C-ATPases). Movements of the three cytoplasmic domains (P, N, and A) and intramembrane region (M) of the ATPase are accompanied by changes in ATPase-subunit binding affinity. The E₁ form, which has a relatively low affinity for the subunit, is accessible for ligands from the cytosol (unknown for P₄-ATPases; Na⁺ or H⁺ for P_2C-ATPases). Binding of ligand promotes phosphorylation of E₁ to create E₁P (not shown). During conversion of E₁P to E₂P, the ligands are discharged to the exoplasmic side, and counter-transported ligands (phospholipid for P₄-ATPases; K⁺ for P_2C-ATPases) can now bind. This is accompanied by a tighter association of the ATPase to the subunit, presumably involving a high affinity interaction between the ATPase and the large ectodomain of the subunit (49, 53).⁵ The latter may contribute to formation of the ligand-binding site or serve as a lid to close access to the ligand-binding site from the exoplasmic side. Failure to achieve this specific arrangement may block dephosphorylation of E₂P, hence preventing the ATPase from continuing successfully through the remainder of the cycle. During reversion to the E₁ state, counter-transported ligands are released to the cytoplasmic side. See “Discussion” for further details. PL, phospholipid; N, nucleotide-binding domain; P, phosphorylation domain; A, actuator domain; M, intramembrane domain.