The Involvement of Protein-Protein Interactions in the Mechanism of the Na+,K+-ATPase

Abstract

The Na+,K+-ATPase (or sodium pump) was the first ion pump to be discovered (Skou, 1957) and it is one of the most fundametally important enzymes of animal physiology. The electrochemical potential for Na+, which the enzyme maintains, is used as the driving force for numerous secondary transport systems, e.g. voltage-sensitive Na+ channels in nerve. ATP provides the energy source to drive ion pumping. However, it also plays a crucial allosteric role, accelerating significantly the enzyme's rate determining E2-E1 transition and the associated release of K+ ions to the cytoplasm. Based on the results of stopped-flow kinetic experiments and recently published crystal structural data for the related enzyme, the sarcoplasmic reticulum Ca2+-ATPase, it is suggested that the allosteric role of ATP in the mechanism of the Na+,K+-ATPase can be explained by an ATP-induced closing of the cytoplasmic domains of the enzyme which relieves steric hindrance arising from interactions between neighbouring pump molecules within the native membrane environment and hence an acceleration of the E2-E1 conformational change (Clarke, 2009). In the presence of millimolar concentrations of ATP, therefore, it is proposed that the enzyme functions as a monomer (alpha-beta protomer), whereas at low ATP concentrations it functions as a dimer ((alpha-beta)2 diprotomer) or higher aggregate. The physiological advantage of protein-protein interactions is still unclear, but a possibility is that they may lead to an enhancement of the enzyme's ATP affinity and allow it to continue functioning even under hypoxic conditions.Skou JC. (1957) Biochimica et Biophysica Acta, 23: 394-401.Clarke RJ (2009) European Biophysics Journal, in press.