Why we must move on from the E1E2 model for the reaction cycle of the P-type ATPases

Recent progress regarding the structure of the Ca(2+)-translocating ATPase of sarcoplasmic reticulum in several conformational states, and a substantial accumulation of biochemical information about this and other P-type ATPases, have put everything in place for the final convergence of biochemistry and structure that will lead to a complete understanding of the molecular mechanism of these membrane transport enzymes. But the common paradigm used to describe the reaction cycle of the P-type ATPases, the E1E2 model, is seriously flawed, and this is hindering our progress toward this goal. In this paper, it is first shown why the E1E2 model must be discarded. This is followed by a description of the P-type ATPase catalytic cycle that is much more consistent with the structural and biochemical information now available for these enzymes, and also brings to light the origin of the forces that drive the key reaction in the active transport cycle where high-affinity ion-binding sites are converted to low-affinity binding sites capable of releasing the transported ions against a considerable concentration gradient. This new model will therefore serve us better as we seek to unravel the final details of the molecular mechanism of active ion transport catalyzed by these enzymes. It is thus time to move on from the traditional E1E2 model.