Cell Membrane Manipulation By Scramblases

Since the seminal paper describing the cell membranes via the fluid-mosaic model [1], there has been continued interest in membrane composition and its physiological importance.  Soon after, it was first hypothesized that the lipids within the membranes existed in an asymmetric state, which was shown using intact vs compromised red blood cells[2].  Importantly, it was shown that phospholipid composition, in particular, phosphatidylserine (PS) and phosphatidyl ethanolamine (PE) localize primarily on the cytoplasmic leaflet of the plasma membrane.  Conversely, other phospholipids such as phosphatidylcholine (PC) and sphingomyelin (SP) are concentrated on the outer leaflet. Passive, transverse movement of phospholipids occurs on the scale of many hours, and it is unlikely the distinct asymmetric pattern of phospholipids could be achieved without a catalytic mediator (reviewed in [3]).  This led to the postulation that active transporters likely existed, and soon thereafter ATP-dependent lipid pumps like flippases and floppases were discovered. Additionally, ATP-independent but Ca2+-dependent lipid channels were also identified, and unlike the lipid pumps which move specific phospholipids in a specific direction [4], scramblases move phospholipids bidirectionally (see figure 1).  Lipid asymmetry is critical for many physiologic processes, so one may wonder what the benefit of diminishing asymmetry via scramblases is. Below we discuss the physiologic role of scramblases and their structural features.

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