Trends in Biochemical Sciences
Rethinking the P-type ATPase problem
Section snippets
The E1E2 model
A description of the E1E2 model for the P-type ATPase reaction cycle, or a reference to it, can be found in virtually all of the articles that have been published about the P-type ATPases since it was formalized in the oft-cited review of DeMeis and Vianna [9]. The model emerged around the same time as the purely conformational two-state energy coupling model of Jardetzky [10], and has many features in common with it. Briefly, it purports the existence of two, and only two, conformational
A more useful model
If the E1E2 dogma can be mentally put aside, it becomes possible to think about the P-type ATPase reaction cycle in a more rational way that is based upon established principles of enzyme catalysis and therefore of more certain heuristic value. This has the added distinct advantage of explicit stipulation of the driving forces for the individual steps, which is essential for a true understanding of any mechanism. A model arising from such considerations is shown in Figure 1. The reaction cycle
Ramifications of the new model
The scheme presented in Figure 1 thus comprises a straightforward cytoplasmic ion-binding reaction for which the atomic structures of both reactants and product are known, and a few additional steps that follow as expected from established principles of enzyme catalysis. It is simple, completely consistent with all of the experimental facts, and almost certainly correct. It should therefore be valuable for the interpretation of future experimental results and reinterpretation of past ones. It
Molecular mechanism of energy coupling
The preceding analysis reduces the quest for an understanding of the molecular mechanism of the P-type ATPases to a single critical step in the catalytic cycle: the E∼PCa2 to TSII reaction. In this reaction, the phosphoryl group of the covalent phosphoenzyme intermediate becomes more tightly bound, and the resulting decrease in chemical potential of the bound phosphoryl group is used to increase the chemical potential of the bound ions, thereby affecting their release to the far side of the
Concluding remarks
The traditional E1E2 model for the reaction cycle of the P-type ATPases has outlived its usefulness and should be replaced. The revised model presented here is more accurate, is based upon established principles of enzyme catalysis, stipulates the forces that drive the individual reaction steps and sheds new light on the nature of the energy coupling reaction. It should therefore be more useful for the interpretation of experimental results and as a guide toward eventual molecular understanding
Acknowledgements
This work was supported by USPHS NIH grant #GM24784.
References (25)
- et al.
Ion motive ATPases. I. Ubiquity, properties, and significance to cell function
TIBS
(1987) The influence of some cations on an adenosine triphosphatase from peripheral nerves
Biochim. Biophys. Acta
(1957)- et al.
Primary ion pumps
Curr. Opin. Cell Biol.
(1990) Structural organization, ion transport, and energy transduction of P-type ATPases
Biochim. Biophys. Acta
(1996)Low-temperature studies of the sarcoplasmic reticulum calcium pump. Mechanism of calcium binding
Biochim. Biophys. Acta
(1982)Effect of magnesium on the calcium-dependent transient kinetics of sarcoplasmic reticulum ATPase, studied by stopped flow fluorescence and phosphorylation
J. Biol. Chem.
(1983)How does a calcium pump pump calcium?
J. Biol. Chem.
(1989)Oligovanadate binding to sarcoplasmic reticulum ATPase. Evidence for substrate analogue behavior
J. Biol. Chem.
(1986)A structural model for the catalytic cycle of Ca2+-ATPase
J. Mol. Biol.
(2002)Binding energy and catalysis: a lesson from protein engineering of the tyrosyl-tRNA synthetase
Trends Biochem. Sci.
(1986)
Site-directed mutagenesis studies of energy coupling in the sarcoplasmic reticulum Ca2+-ATPase
Biochim. Biophys. Acta
P-type H++- and Ca2+-ATPases in plant cells
Ann. N. Y. Acad. Sci.
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2013, Journal of Biological ChemistryCitation Excerpt :This indicates that the N-domain environment is more hydrophobic in the presence of Ca2+ (E1Ca). Scarborough (73) has observed the inadequacy of the E1/E2 nomenclature to describe the intermediates involved in the reaction cycle of P-type ATPases. In this work, we have demonstrated the existence of species of PMCA that can be seen as different conformers, depending on whether the measurements were sensing changes in the cytoplasmic (experiments with TNP-ATP) or in the transmembrane ([125I]TID-PC/16 photolabeling) domains of the enzyme.
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