Molecular mechanisms of K+ selectivity in Na/K pump

The sodium–potassium (Na/K) pump plays an essential role in maintaining cell volume and secondary active transport of other solutes by establishing the Na+ and K+ concentration gradients across the plasma membrane of animal cells. The recently determined crystal structures of the Na/K pump to atomic resolution provide a new impetus to investigate molecular determinants governing the binding of Na+ and K+ ions and conformational transitions during the functional cycle. The pump cycle is generally described by the alternating access mechanism, in which the pump toggles between different conformational states, where ions can bind from either the intracellular or the extracellular side. However, important issues concerning the selectivity of the Na/K pump remain to be addressed. In particular, two out of the three binding sites are shared between Na+ and K+ and it is not clear how the protein is able to select K+ over Na+ when it is in the outwardly facing phosphorylated conformation (E2P), and Na+ over K+ when it is in the inwardly facing conformation (E1). In this review article, we will first briefly review the recent advancement in understanding the microscopic mechanism of K+ selectivity in the Na/K pump at the E2.Pi state and then outline the remaining challenges to be addressed about ion selectivity.