Mechanism and significance of P4 ATPase-catalyzed lipid transport: Lessons from a Na+/K+-pump

Members of the P-4 subfamily of P-type ATPases are believed to catalyze phospholipid transport across membrane bilayers, a process influencing a host of cellular functions. Atomic structures and functional analysis of P-type ATPases that pump small cations and metal ions revealed a transport mechanism that appears to be conserved throughout the family. A challenging problem is to understand how this mechanism is adapted in P-4 ATPases to flip phospholipids. P-4 ATPases form oligomeric complexes with members of the CDC50 protein family. While formation of these complexes is required for P-4 ATPase export from the endoplasmic reticulum, little is known about the functional role of the CDC50 subunits. The Na+/K+-ATPase and closely-related H+/K+-ATPase are the only other P-type pumps that are oligomeric, comprising mandatory beta-subunits that are strikingly reminiscent of CDC50 proteins. Besides serving a role in the functional maturation of the catalytic alpha-subunit, the beta-subunit also contributes specifically to intrinsic transport properties of the Na+/K+ pump. As beta-subunits and CDC50 proteins likely adopted similar structures to accomplish analogous tasks, current knowledge of the Na+/K+-ATPase provides a useful guide for understanding the inner workings of the P-4 ATPase class of lipid pumps. (C) 2009 Elsevier B.V. All rights reserved.