scramblases

Scramblases are a diverse group of membrane proteins that catalyze the bidirectional movement of phospholipids between the two leaflets of a phospholipid bilayer, disrupting the typical asymmetry of cellular membranes. Unlike flippases and floppases, scramblases generally do not require energy input to move lipids and can be activated by cellular signals or stress.

Several protein families are associated with lipid scrambling. The TMEM16 family, also known as anoctamins, includes Ca2+-activated phospholipid scramblases such as TMEM16F, which can mediate phosphatidylserine exposure in platelets and other cells, sometimes with concurrent ion channel activity. The XKR family, including XKR8, is activated by caspase cleavage during apoptosis and promotes PS exposure on the cell surface, marking cells for clearance. The phospholipid scramblase (PLSCR) family (PLSCR1–PLSCR4) has been studied for Ca2+-dependent scrambling in the plasma membrane, though their precise mechanisms and physiological roles remain under debate. In the endoplasmic reticulum, scramblases such as TMEM41B and VMP1 facilitate bidirectional lipid movement and contribute to autophagosome formation and membrane remodeling.

Physiological roles of scramblases are diverse. Externalization of phosphatidylserine serves in coagulation and the recognition of dying cells, while scramblases in the ER support lipid distribution critical for organelle biogenesis and autophagy. Given their involvement in membrane dynamics, scramblases are active research targets for understanding cell signaling, apoptosis, and intracellular trafficking.

Research methods to study scramblases include lipid-flipping assays with fluorescent or labeled lipids and monitoring surface exposure of phosphatidylserine by annexin V binding.