12.6:
Membrane Asymmetry Regulating Transporters
Membrane asymmetry is regulated by three types of transporters that translocate phospholipids through the bilayer.
Flippases are ATP-dependent lipid importers that transfer phosphatidylserine and phosphatidylethanolamine from the outer to the inner layer.
Floppases are ATP-dependent non-specific lipid exporters that transport lipids from the inner to the outer layer. Both flippase and floppase play an important role in generating membrane asymmetry.
Scramblases are ATP-independent transporters that allow the random movement of lipids in both layers, thereby reducing membrane asymmetry. In erythrocytes, scramblases are inactive at normal physiological levels of intracellular calcium and become activated when the calcium ion concentration increases.
The activation of scramblases can transfer phosphatidylserine from the inner to the outer membrane layer. The outward exposure of phosphatidylserine marks erythrocytes for a suicidal death known as eryptosis and triggers their removal by macrophages.
12.6:
Membrane Asymmetry Regulating Transporters
Enzymes like flippase, floppase, and scramblase transfer phospholipids from one layer to another in the membrane, thereby affecting membrane asymmetry.
Flippase
Eukaryotic flippases are type-IV P-type ATPases or P4-ATPases belonging to P-type ATPase family proteins that are membrane-bound pumps involved in the ATP-mediated transport of ions and molecules across the membrane. Flippases flip specific phospholipids from the outer to the inner leaflet of a membrane. All P4-ATPases have one transmembrane domain containing ten transmembrane α-helices and three cytoplasmic domains. The three cytoplasmic domains include a nucleotide-binding domain, a phosphorylation domain, and an actuator domain involved in the dephosphorylation step.
Floppase
Floppases belong to the ATP-binding cassette or ABC-transporter family proteins that transfer a variety of phospholipids from the inner to the outer leaflet of a membrane. Some of the essential proteins of this family are ABCA1, ABCA4, ABCB1, and ABCB4. ABCA1 floppase can transfer cholesterol from the inner to the outer leaflet of the membrane, and its mutation can result in Tangier disease.
Scramblase
Scramblase, unlike flippase and floppase, can do the bidirectional transfer of phospholipids in the membrane without using energy from ATP hydrolysis. There are two types of scramblases in the cell – transmembrane protein 16F (TMEM16F) and XK-related protein 8 (Xkr8). TMEM16F scramblase is located within the platelet membrane and needs a high concentration of calcium ions for activation. In contrast, caspase activates Xkr8 in the cell membrane during apoptosis. The defective expression of scramblase results in a bleeding disorder called Scott syndrome.