Asymmetric distribution of membrane lipids.
In eukaryotic cells, phospholipids on the plasma membrane are asymmetrically distributed with phosphatidylcholine (PC) and sphingomyelin (SPH) predominantly residing in the outer leaflet, whereas the aminophospholipids phosphatidylethanolamine (PE) and phosphatidylserine (PS) are enriched in the inner leaflet.
How is the membrane lipid asymmetry established?
This asymmetry is delicately maintained by two types of ATP-driven lipid translocases: flippases and floppases actively catalyze the trans-bilayer movement of PS/PE to the inner leaflet and PC/SPH to the outer leaflet, respectively.
What are lipid scramblases?
Under certain physiological conditions such as platelet activation, neurotransmitter release, sperm capacitation or apoptosis, a third type of lipid translocase called scramblases can be activated, which rapidly and nonselectively flip-flop all phospholipid species. Different from flippases and floppases, the activation of lipid scramblases does not require ATP hydrolysis. Instead, elevation of intracellular calcium or activation of caspase cascades during apoptosis can activate scramblases. Recent studies from the Nagata group suggest that TMEM16F and Xkr8 are responsible for the calcium-activated and apoptosis-induced lipid scrambling, respectively.
What are the consequences of lipid scrambling?
Lipid composition asymmetry defines the physical and chemical properties of the plasma membrane, as well as its interactions with intracellular and extracellular molecules. Scrambling of lipid species destroys membrane lipid asymmetry and results in the exposure of the negatively charged PS to the cell surface. PS exposure has been shown to be important in various physiological processes such as platelet activation, apoptosis, neurotransmitter release and sperm capacitation. For instance, the exposed PS in platelets serves as a platform to recruit key factors to convert prothrombin to thrombin, a key step in the blood clotting cascade. On the other hand, the exposed PS in apoptotic cells can serve as an “eat-me” signal to attract phagocytes to clean the post-apoptotic cell corpses.