Phospholipid asymmetry is a fundamental feature of the eukaryotic cell plasma membrane. The aminophospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE) are restricted to the cytosolic leaflet of the plasma membrane while sphingolipids and phosphatidylcholine are enriched in the extracellular leaflet. Regulated exposure of PS and PE on the extracellular leaflet contributes to cell signaling, cytokinesis, blood clotting, apoptotic cell corpse removal and host-viral interactions. Phospholipid asymmetry is established by type IV P-type ATPases (P4-ATPases), a large family of flippases that pump aminophospholipids from the exofacial leaflet to the cytosolic leaflet of the membrane bilayer. The P4-ATPase subfamily is highly conserved among eukaryotes and these pumps have been implicated in pathological conditions such as obesity and type 2 diabetes, intrahepatic cholestasis, progressive hearing loss, immune deficiency, mental disability, hepatic cancer and male infertility. In addition to their role in establishing membrane asymmetry, P4-ATPases are also critical components of the vesicle-mediated protein trafficking machinery within the Golgi and endosomal system. Through their role in protein trafficking, the P4-ATPases could have a strong influence on type 2 diabetes and insulin resistance, as well as the downregulation of growth factor receptors needed to prevent the uncontrolled cell growth that is characteristic of cancer. The proposed studies will define how the P4-ATPases establish membrane asymmetry and will be invaluable to our understanding of the pathologies associated with P4-ATPase deficiencies.
Defects in human P4-ATPases cause mental retardation and familial intrahepatic cholestasis. Studies with mice have further implicated P4-ATPases in immune deficiency, type 2 diabetes, hearing loss and hepatic cancer. Defining the mechanism of P4-ATPase function will further our understanding of these diseases.
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