Rethinking the P-type ATPase problem.

There are very good reasons to stop thinking about the molecular mechanism of the P-type ion-translocating ATPases in terms of the traditional E1E2 model and to start thinking about it in more progressive ways. This makes it possible to see the ion-transport cycle as a rational series of discrete steps with well defined driving forces, including the crucial energy transduction step, where the chemical energy of ATP hydrolysis is exchanged for the osmotic energy of an ion gradient. Importantly, although major enzyme conformational changes accompany each of these steps, none of them drive the energy coupling reaction. Thus, neither the E1E2 model nor conformational energy coupling, the cornerstones of traditional thinking about the P-type ATPases, are reliable paradigms for future efforts to understand how these transporters work. Alternatives must be seriously considered.