Towards defining the substrate of orphan P5A-ATPases.
BACKGROUND
P-type ATPases are ubiquitous ion and lipid pumps found in cellular membranes. P5A-ATPases constitute a poorly characterized subfamily of P-type ATPases present in all eukaryotic organisms but for which a transported substrate remains to be identified.


METHODS
This review aims to discuss the available evidence which could lead to identification of possible substrates of P5A-ATPases.


CONCLUSIONS
The complex phenotypes resulting from the loss of P5A-ATPases in model organisms can be explained by a role of the P5A-ATPase in the endoplasmic reticulum (ER), where loss of function leads to broad and unspecific phenotypes related to the impairment of basic ER functions such as protein folding and processing. Genetic interactions in Saccharomyces cerevisiae point to a role of the endogenous P5A-ATPase Spf1p in separation of charges in the ER, in sterol metabolism, and in insertion of tail-anchored proteins in the ER membrane. A role for P5A-ATPases in vesicle formation would explain why sterol transport and distribution are affected in knock out cells, which in turn has a negative impact on the spontaneous insertion of tail-anchored proteins. It would also explain why secretory proteins destined for the Golgi and the cell wall have difficulties in reaching their final destination. Cations and phospholipids could both be transported substrates of P5A-ATPases and as each carry charges, transport of either might explain why a charge difference arises across the ER membrane.


CONCLUSIONS
Identification of the substrate of P5A-ATPases would throw light on an important general process in the ER that is still not fully understood. This article is part of a Special Issue entitled Structural biochemistry and biophysics of membrane proteins.
Centre for Membrane Pumps in Cells and Disease-PUMPkin, Department of Plant and Environmental Sciences, University of Copenhagen, Thorvaldsensvej 40, DK-1871 Frederiksberg C, Denmark.
Danny Mollerup
DM
Sørensen
Centre for Membrane Pumps in Cells and Disease-PUMPkin, Department of Plant and Environmental Sciences, University of Copenhagen, Thorvaldsensvej 40, DK-1871 Frederiksberg C, Denmark.
Henrik Waldal
HW
Holen
Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, Katholieke Universiteit Leuven, Herestraat 49, Box 802, B3000 Leuven, Belgium.
Tine
T
Holemans
Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, Katholieke Universiteit Leuven, Herestraat 49, Box 802, B3000 Leuven, Belgium.
Peter
P
Vangheluwe
Centre for Membrane Pumps in Cells and Disease-PUMPkin, Department of Plant and Environmental Sciences, University of Copenhagen, Thorvaldsensvej 40, DK-1871 Frederiksberg C, Denmark. Electronic address: palmgren@plen.ku.dk.
Michael G
MG
Palmgren
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D004721:Endoplasmic Reticulum / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism; D013379:Substrate Specificity
D018528:ATP-Binding Cassette Transporters; C406793:SPF1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D013261:Sterols; D000251:Adenosine Triphosphatases
Endoplasmic reticulum; Membrane transport; P5A-ATPase; Primary active pump; Unfolded protein response