Fig. 3.

Domain structure, organization, and proposed mechanism of P₄-ATPases. (A) P₄-ATPases adopt a four domain structure consisting of cytosolic A (actuator), P (phosphorylation), and N (nucleotide binding) domains as well as a M (membrane) domain consisting of 10 membrane spanning segments and containing the translocation pathway. Absolutely conserved motifs are shown. P-type ATPases are phosphorylated at the aspartic acid of the invariant DKTG motif. The glutamic acid of the DGE motif in the A domain catalyzes dephosphorylation. The CDC50 β-subunit is shown containing four N-linked glycosylations and two disulfide linkages in the large E (extracellular) domain. (B) P-type ATPases exist in four primary conformations. Binding of ATP and phosphorylation of the P-domain in the E₁ form converts the enzyme to E₁P. During the E₁P to E₂P transition, the A-domain rotates allowing lipids to bind to an extracellular binding site in the M-domain in the E₂P conformation. Dephosphorylation of E₂P drives the translocation of the lipid through the membrane to the cytoplasmic side. The enzyme is converted back to the E₁ form when the A-domain moves away from the P-domain. The role of CDC50 (green) is unknown.