Topology and reaction schemes of flippase and Na+,K+-ATPase. (A) Diagram of P4-ATPase topology indicating P-type ATPase domains and residues studied here by mutagenesis, as well as K873 of M5 studied previously (12). (B) Proposed flippase reaction cycle. (C) Reaction cycle of Na+,K+-ATPase [Post-Albers scheme (10, 11)]. E1, E1P, E2P, and E2 are the major enzyme forms, the P indicating phosphorylation.