User:Ray1590/Flippase

Lead
Flippases are transmembrane lipid transporter proteins located in the membrane. They are responsible for aiding the movement of phospholipid molecules between the two leaflets that compose a cell's membrane (transverse diffusion, also known as a "flip-flop" transition). Flippases responses to move the lipids from outer layer of membrane to inner layer.

Lateral and Transverse Movements
In organisms, the cell membrane consists of a phospholipid bilayer. In the bilayer, the phospholipid molecule is movable. These movements are categorized into two types, Lateral movements and Transverse movements (also called Flip-Flop). The first is the lateral movement, where the phospholipid moves horizontally on the same side of the membrane. Lateral movement is very fast, with an average speed of up to 2 mm per second. Transverse movement is the movement of phospholipid molecule from one side of the membrane to the other. Transverse movement is very slow, and without the assistance of enzymes, it may only occur even once a month. The reason is that the polar head groups of phospholipid molecule cannot pass easily through the hydrophobic center of the bilayer, limiting their diffusion in this dimension.

Although Flip-Flop is slow, This movement is necessary to continue their normal function of growth and mobility. The possibility of active maintenance of an asymmetric distribution of molecules in the phospholipid bilayer was predicted in the early 1970s by Mark Bretscher. Asymmetry molecule of membrane has been proved to related to the broad physiological implications of lipid asymmetry, from cell shape determination to critical signaling processes like blood coagulation and apoptosis. Many cells maintain asymmetric distributions of phospholipids between their cytoplasmic and exoplasmic membrane leaflets. The loss of asymmetry, in particular the appearance of the anionic phospholipid phosphatidylserine on the exoplasmic face, can serve as an early indicator of apoptosis and as a signal for efferocytosis.

Different Classes of Lipid Transporters
Lipid transporters transport or flip lipids across the bilayers. There exist three major classes of Lipid Transporters:


 * 1) P-type Flippase
 * 2) ABC Flippase
 * 3) Scramblases

P-type Flippase and ABC Flippase are energy-dependent (ATP) enzyme that can create lipid asymmetry and transport specific lipids. Scramblases are energy-independent enzyme that can dissipate lipid asymmetry and have a broad lipid specificity. Flippases belong to P-type Flippase and it moves lipids from the exoplasmic to the cytosolic face .



Structure and Domains of Flippase
Flippase contains a large transmembrane Segments and two major subunits, a catalytic domain called Alpha-Subunits and a accessory domain named Beta-Subunits. Transmembrane Segments contains 10 transmembrane Alpha helix and this domain together with Beta-subunit plays important role in stability, localization and recognition of substrate (lipid) of Flippase. Alpha-Subunits included A, P and N domains and each of them responses to different function of flippase. A-domain is an actuator segment of Flippase, its function is to dissociate the Lipid by dephosphorylation. P-domain responses to activate the Flip-Flop by phosphorylation. Last domain is N-domain, which job is to bind to substrate (lipid).

Mechanism of Flippase
In order to bind specific lipid on the outer layer of membrane, flippase need to be phosphorylated by ATP on P-domain. Then the target lipid will bind to N-domain of Flippase. With substrate-binding and phosphorylation, Flippases undergo conformational change from E1 to E2 (E1 and E2 stand for different conformations of Flippases). E2 conformation of Flippase then be dephosphorylated by A-domain and the lipid dissociate from Flippase and successfully transports to inner layer of membrane. Finally, conformational change on Flippase from E2 back to E1 and ready to next cycle of lipid transportation.