FUNCTIONAL SIGNIFICANCE OF THE -SUBUNIT FOR HETERODIMERIC P-TYPE ATPases

We have reviewed the structural and functional role of the -subunit in a subfamily of the P-ATPases known as the / -heterodimeric, cation-exchange ATPases. The subfamily consists of the various isoforms of Na+/K+ATPase and H+/K+-ATPase, both of which pump a cation out of the cell (Na+ or H+, respectively) in recycle exchange for K+. Much of the earlier work has emphasized the functional activities of the -subunit, which shares many characteristics with the broader P-ATPase family. It is now clear that the glycosylated -subunit is an essential component of the cation-exchange ATPase subfamily. All -subunit isoforms have three highly conserved disulfide bonds within the extracellular domain that serve to stabilize the -subunit, / interaction and functional activity of the holoenzyme. Evidence strongly suggests that the -subunit is involved in the K+-dependent reactions of the enzymes, such as the E1–E2 transition and K+ occlusion, and that the extracellular domain of the -subunit plays an important role in determining the kinetics of K+ interaction. In most vertebrate cells, the unassociated subunit is restricted to the endoplasmic reticulum (ER), and assembly of the / complex occurs within the ER. Signals for exiting the ER and directing the correct intracellular trafficking are primarily determined by the subunit; Na+/K+-ATPase typically terminates in the plasma membrane facing the basolateral membrane, whereas all isoforms of H+/K+-ATPase terminate in the apical membrane. The C-terminal extracellular domain of the subunit is important for proper interaction with the subunit and for correct intracellular trafficking. Oligosaccharides on the -subunit are not essential for enzyme function, but do serve to enhance the efficiency of / association by increasing the lifetime of the unassociated -subunit and the stability of the / complex to tryptic attack. We propose that highly specialized glycosylation on the -subunit of the gastric H+/K+-ATPase may help to protect that enzyme from the harsh extracellular environment of the stomach.