P5 ATPases: ubiquitous pumps having no assigned substrate

As genome sequences began to accumulate in the late nineties, results from data mining, using conserved P-type ATPase sequence motifs as search strings, made it apparent that a group of eukaryotic sequences clustered together as the fifth subfamily of P-type ATPases (P5 ATPases). Although several members of this family are involved in severe human diseases the substrate specificity of any P5 pump remains a mystery.

The diversity of phenotypes associated with disruption of P5 ATPases suggests that the effects are indirect and influence several cellular components. This implies a basal function in the cellular machinery, which would be compatible with an essential role in the initial fate of newly folded proteins in the ER membrane or, in case of soluble proteins, in the ER lumen, that are to be transported to other cellular destinations. Such a general function would explain the problems associated with overexpression of P5 ATPases in cells and calls for careful design of heterologous expression systems.