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Abstract
The plasma membrane (PM) is composed of a complex lipid mixture that forms heterogeneous membrane environments. Yet how small-scale lipid organization controls physiological events at the PM remains largely unknown. Here, we show that ORP/Osh lipid exchange proteins are critical for the synthesis of phosphatidylinositol (4,5)-bisphosphate, PI(4,5)P2, a key regulator of dynamic events at the PM. In real-time assays, we find that unsaturated phosphatidylserine (PS) and sterols, both ORP/Osh protein ligands, synergistically stimulate phosphatidylinositol 4-phosphate 5-kinase (PIP5K) activity. Our biophysical and simulation analyses further reveal an unconventional co-segregation of unsaturated PS and phosphatidylinositol 4-phosphate (PI4P) species in sterol-containing membrane bilayers. Moreover, we show that Osh protein-mediated unsaturated PI4P/PS membrane lipid organization is sensed by the PIP5K specificity loop. Thus, ORP/Osh family members create an unsaturated phospholipid nanoscale environment that drives PIP5K activity and PI(4,5)P2 synthesis that ultimately controls global PM organization and dynamics.
Highlights
Distinctions in membrane lipid composition establish organelle identity in eukaryotic cells (Bigay and Antonny, 2012)
In real-time assays, we find that unsaturated phosphatidylserine (PS) and sterols, both Osh protein ligands, synergistically stimulate phosphatidylinositol 4-phosphate 5-kinase (PIP5K) activity
Using in vivo imaging approaches and molecular dynamics simulations, we show that Osh proteinmediated unsaturated phosphatidylinositol 4-phosphate (PI4P) and PS membrane lipid organization is sensed by the PIP5K specificity loop
Summary
Distinctions in membrane lipid composition establish organelle identity in eukaryotic cells (Bigay and Antonny, 2012). The cytoplasmic leaflet of the ER membrane is defined by low sterol content and is high in unsaturated phospholipids. The cytoplasmic leaflet of the PM is enriched in distinct lipids that serve as hallmarks for its identity, including sterols and the anionic phospholipid phosphatidylserine (PS). Phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] is another key determinant for PM identity and function (Balla, 2013; Di Paolo and De Camilli, 2006). PI(4,5)P2 has vital roles in many events at the PM, including exocytosis, endocytosis, cytoskeletal dynamics, cytokinesis, ion channel regulation, and the generation of second messenger molecules (Balla, 2013; Di Paolo and De Camilli, 2006). Physiological roles for PI(4,5)P2 at the PM have been intensely studied, less is known about the regulation of PI(4,5)P2 metabolism
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