Ion Transport by the Sodium Pump

Abstract

The first crystal structure of the Na+,K+-ATPase revealed the potassium-bound form of the pig kidney enzyme at 3.5 A resolution. This large membrane protein complex consists of an alpha subunit similar to the Ca2+-ATPase, a heavily glycosylated beta subunit and a small regulatory gamma subunit (also known as FXYD2). The electrogenic transport performed by the Na+,K+-ATPase causes extrusion of three sodium ions and uptake of two potassium ions per ATP split. The gradients thus formed are of fundamental importance in physiology as they control ionic conditions in the cell and energise osmotic potentials, secondary transport schemes and ionotropic signalling.A surprising finding from the Na+,K+-ATPase structure was the docking of two conserved tyrosine residues at the C-terminus of the alpha subunit into the transmembrane domain, hinting that this was a previously unidentified regulatory element. Several mutations causing human neurological syndromes have subsequently been mapped to the C-terminal structure element, also clearly indicating that conservation of the structure is important for pump function.Mutational analysis confirmed this and prompted our further analysis by electrophysiology and molecular dynamics simulations, which have shown a profound effect of the C-terminus on the electrogenic transport properties. We further propose that the C-terminal region forms a binding pocket that can be exploited for pharmacological intervention in cardiovascular and neurological disease.