Phospholipid Flippase Activities and Substrate Specificities of Human Type IV P-type ATPases Localized to the Plasma Membrane

Abstract

Background:The enzymatic activities of mammalian P4-ATPases are incompletely characterized. Results: ATP11A and ATP11C catalyze flipping of NBD-PS and NBD-PE, whereas ATP8B1 preferentially catalyzes flipping of NBD-PC. Furthermore, some PFIC1 mutants of ATP8B1 failed to flip PC. Conclusion: ATP11A/ATP11C and ATP8B1/ATP8B2 preferentially translocate aminophospholipids and PC, respectively. Significance: This is the first evidence showing that the PC-flipping activity of ATP8B1 is associated with the episode of PFIC1.

Transbilayer lipid distribution in nano scale

“…These results suggest that PC in the outer and inner leaflet do not coordinate across the bilayer in caveolae. Recently it has been reported that type IV P-type ATPase ATP8B1/ATP8B2 preferentially translocates PC from the outer to the inner leaflet of the plasma membrane (Takatsu et al, 2014). Our results suggest that caveolae are the site of the transbilayer movement of PC in HSFs.…”

Switching head group selectivity in mammalian sphingolipid biosynthesis by active-site engineering of sphingomyelin synthases

“…Eukaryotic cells, from mammals to yeast, contain ATPfueled flippases that translocate PE and PC from the exo plasmic to the cytosolic leaflet of late secretory organelles (33)(34)(35)(36). These activities may influence SMSmediated SM and CPE production by limiting the amount of PC and PE available for consumption by SMS enzymes.…”

Specific mutations in mammalian P4‐ATPase ATP8A2 catalytic subunit entail differential glycosylation of the accessory CDC50A subunit

“…Association with CDC50 proteins is crucial to the stability, subcellular localization and flippase activity of P4-ATPases [23,24,28,33,35], but the available evidence does not indicate a role for CDC50 proteins in determination of substrate specificity [38,[41][42][43]. The interaction between yeast flippase Drs2 and its specific partner Cdc50p was shown to fluctuate during the transport cycle, with the strongest association occurring in the E 2 P conformation, in which the P4-ATPase binds its phospholipid substrate from the exoplasmic membrane leaflet [22,24].…”