P4 ATPases: Flippases in Health and Disease

Abstract

P4 ATPases catalyze the translocation of phospholipids from the exoplasmic to the cytosolic leaflet of biological membranes, a process termed “lipid flipping”. Accumulating evidence obtained in lower eukaryotes points to an important role for P4 ATPases in vesicular protein trafficking. The human genome encodes fourteen P4 ATPases (fifteen in mouse) of which the cellular and physiological functions are slowly emerging. Thus far, deficiencies of at least two P4 ATPases, ATP8B1 and ATP8A2, are the cause of severe human disease. However, various mouse models and in vitro studies are contributing to our understanding of the cellular and physiological functions of P4-ATPases. This review summarizes current knowledge on the basic function of these phospholipid translocating proteins, their proposed action in intracellular vesicle transport and their physiological role.

Phospholipid flippase ATP8A2 is required for normal visual and auditory function and photoreceptor and spiral ganglion cell survival

“…Flipping of aminophospholipids has been implicated in establishing phospholipid asymmetry in biological membranes and generating the membrane curvature required for many cellular processes (Coleman et al, 2013;Graham and Kozlov, 2010;Puts and Holthuis, 2009;Sebastian et al, 2012;van der Mark et al, 2013).…”

Mice Deficient in the Putative Phospholipid Flippase ATP11C Exhibit Altered Erythrocyte Shape, Anemia, and Reduced Erythrocyte Life Span*

“…Studies in yeast suggest that members of the P4-type ATPase family serve as flippases, selectively translocating PS and, to a lesser extent, phosphatidylethanolamine into the cytoplasmic leaflet of cell membranes (11,12,18). Although there are 15 members of the P4-type ATPase family in mice (14 members in humans) (12), their biological functions are largely unknown (19), and so far, only a few flippases have been linked to biological functions in mammalians. Among these, mutations in the gene encoding ATP8A2 in humans and mice have been shown to cause neurological disorders (20 -22).…”

Sphingomyelin Depletion Impairs Anionic Phospholipid Inward Translocation and Induces Cholesterol Efflux

“…The plasma membrane has an asymmetric leaflet-specific distribution of phospholipids with an exclusive enrichment of phosphatidylserine (PS) 2 in the inner leaflet, whereas complex sphingolipids reside mainly on the outer leaflet (1)(2)(3)(4). Several ABC (ATP-binding cassette) proteins mediate the translocation of lipids from the inner to outer leaflet (floppase activity), such as ABCA1, which transports PS to the outer leaflet (4), whereas P-type ATPases are responsible for translocating phospholipids from the outer to inner leaflet (flippase activity) of the plasma membrane (4 -6).…”