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.
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 [1] . 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 [1] . 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 [2] . The possibility of active maintenance of an asymmetric distribution of molecules in the phospholipid bilayer was predicted in the early 1970s by Mark Bretscher [3] . 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 [4] . 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 [5] and as a signal for efferocytosis [6] .
Lipid transporters transport or flip lipids across the bilayers. There exist three major classes of Lipid Transporters:
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 [8] . Flippases belong to P-type Flippase [7] and it moves lipids from the exoplasmic to the cytosolic face [8] .
Flippase contains a large transmembrane Segments and two major subunits, a catalytic domain called Alpha-Subunits and a accessory domain named Beta-Subunits [2] . 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 [2] . 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) [2] .
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) [2] . 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 [2] .
A biological membrane, biomembrane or cell membrane is a selectively permeable membrane that separates the interior of a cell from the external environment or creates intracellular compartments by serving as a boundary between one part of the cell and another. Biological membranes, in the form of eukaryotic cell membranes, consist of a phospholipid bilayer with embedded, integral and peripheral proteins used in communication and transportation of chemicals and ions. The bulk of lipids in a cell membrane provides a fluid matrix for proteins to rotate and laterally diffuse for physiological functioning. Proteins are adapted to high membrane fluidity environment of the lipid bilayer with the presence of an annular lipid shell, consisting of lipid molecules bound tightly to the surface of integral membrane proteins. The cell membranes are different from the isolating tissues formed by layers of cells, such as mucous membranes, basement membranes, and serous membranes.
Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue. Marine phospholipids typically have omega-3 fatty acids EPA and DHA integrated as part of the phospholipid molecule. The phosphate group can be modified with simple organic molecules such as choline, ethanolamine or serine.
ATPases (EC 3.6.1.3, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are a class of enzymes that catalyze the decomposition of ATP into ADP and a free phosphate ion or the inverse reaction. This dephosphorylation reaction releases energy, which the enzyme (in most cases) harnesses to drive other chemical reactions that would not otherwise occur. This process is widely used in all known forms of life.
An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All transmembrane proteins can be classified as IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a significant fraction of the proteins encoded in an organism's genome. Proteins that cross the membrane are surrounded by annular lipids, which are defined as lipids that are in direct contact with a membrane protein. Such proteins can only be separated from the membranes by using detergents, nonpolar solvents, or sometimes denaturing agents.
The lipid bilayer is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many viruses are made of a lipid bilayer, as are the nuclear membrane surrounding the cell nucleus, and membranes of the membrane-bound organelles in the cell. The lipid bilayer is the barrier that keeps ions, proteins and other molecules where they are needed and prevents them from diffusing into areas where they should not be. Lipid bilayers are ideally suited to this role, even though they are only a few nanometers in width, because they are impermeable to most water-soluble (hydrophilic) molecules. Bilayers are particularly impermeable to ions, which allows cells to regulate salt concentrations and pH by transporting ions across their membranes using proteins called ion pumps.
Peripheral membrane proteins, or extrinsic membrane proteins, are membrane proteins that adhere only temporarily to the biological membrane with which they are associated. These proteins attach to integral membrane proteins, or penetrate the peripheral regions of the lipid bilayer. The regulatory protein subunits of many ion channels and transmembrane receptors, for example, may be defined as peripheral membrane proteins. In contrast to integral membrane proteins, peripheral membrane proteins tend to collect in the water-soluble component, or fraction, of all the proteins extracted during a protein purification procedure. Proteins with GPI anchors are an exception to this rule and can have purification properties similar to those of integral membrane proteins.
The fluid mosaic model explains various characteristics regarding the structure of functional cell membranes. According to this biological model, there is a lipid bilayer in which protein molecules are embedded. The phospholipid bilayer gives fluidity and elasticity to the membrane. Small amounts of carbohydrates are also found in the cell membrane. The biological model, which was devised by Seymour Jonathan Singer and Garth L. Nicolson in 1972, describes the cell membrane as a two-dimensional liquid that restricts the lateral diffusion of membrane components. Such domains are defined by the existence of regions within the membrane with special lipid and protein cocoon that promote the formation of lipid rafts or protein and glycoprotein complexes. Another way to define membrane domains is the association of the lipid membrane with the cytoskeleton filaments and the extracellular matrix through membrane proteins. The current model describes important features relevant to many cellular processes, including: cell-cell signaling, apoptosis, cell division, membrane budding, and cell fusion. The fluid mosaic model is the most acceptable model of the plasma membrane. In this definition of the cell membrane, its main function is to act as a barrier between the contents inside the cell and the extracellular environment.
A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembrane proteins; that is they exist permanently within and span the membrane across which they transport substances. The proteins may assist in the movement of substances by facilitated diffusion, active transport, osmosis, or reverse diffusion. The two main types of proteins involved in such transport are broadly categorized as either channels or carriers. Examples of channel/carrier proteins include the GLUT 1 uniporter, sodium channels, and potassium channels. The solute carriers and atypical SLCs are secondary active or facilitative transporters in humans. Collectively membrane transporters and channels are known as the transportome. Transportomes govern cellular influx and efflux of not only ions and nutrients but drugs as well.
Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They enable coupled or cotransport and include antiporters and symporters. In general, cotransporters consist of two out of the three classes of integral membrane proteins known as transporters that move molecules and ions across biomembranes. Uniporters are also transporters but move only one type of molecule down its concentration gradient and are not classified as cotransporters.
The ABC transporters, ATP synthase (ATP)-binding cassette transporters are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. It is represented in all extant phyla, from prokaryotes to humans. ABC transporters belong to translocases.
Glycerophospholipids or phosphoglycerides are glycerol-based phospholipids. They are the main component of biological membranes in eukaryotic cells. They are a type of lipid, of which its composition affects membrane structure and properties. Two major classes are known: those for bacteria and eukaryotes and a separate family for archaea.
Scramblase is a protein responsible for the translocation of phospholipids between the two monolayers of a lipid bilayer of a cell membrane. In humans, phospholipid scramblases (PLSCRs) constitute a family of five homologous proteins that are named as hPLSCR1–hPLSCR5. Scramblases are members of the general family of transmembrane lipid transporters known as flippases. Scramblases are distinct from flippases and floppases. Scramblases, flippases, and floppases are three different types of enzymatic groups of phospholipid transportation enzymes. The inner-leaflet, facing the inside of the cell, contains negatively charged amino-phospholipids and phosphatidylethanolamine. The outer-leaflet, facing the outside environment, contains phosphatidylcholine and sphingomyelin. Scramblase is an enzyme, present in the cell membrane, that can transport (scramble) the negatively charged phospholipids from the inner-leaflet to the outer-leaflet, and vice versa.
Mark Steven Bretscher is a British biological scientist and Fellow of the Royal Society. He worked at the Medical Research Council Laboratory of Molecular Biology in Cambridge, United Kingdom and is currently retired.
Surfactin is a cyclic lipopeptide, commonly used as an antibiotic for its capacity as a surfactant. It is an amphiphile capable of withstanding hydrophilic and hydrophobic environments. The Gram-positive bacterial species Bacillus subtilis produces surfactin for its antibiotic effects against competitors. Surfactin showcases antibacterial, antiviral, antifungal, and hemolytic effects.
The P-type ATPases, also known as E1-E2 ATPases, are a large group of evolutionarily related ion and lipid pumps that are found in bacteria, archaea, and eukaryotes. P-type ATPases are α-helical bundle primary transporters named based upon their ability to catalyze auto- (or self-) phosphorylation (hence P) of a key conserved aspartate residue within the pump and their energy source, adenosine triphosphate (ATP). In addition, they all appear to interconvert between at least two different conformations, denoted by E1 and E2. P-type ATPases fall under the P-type ATPase (P-ATPase) Superfamily (TC# 3.A.3) which, as of early 2016, includes 20 different protein families.
One property of a lipid bilayer is the relative mobility (fluidity) of the individual lipid molecules and how this mobility changes with temperature. This response is known as the phase behavior of the bilayer. Broadly, at a given temperature a lipid bilayer can exist in either a liquid or a solid phase. The solid phase is commonly referred to as a “gel” phase. All lipids have a characteristic temperature at which they undergo a transition (melt) from the gel to liquid phase. In both phases the lipid molecules are constrained to the two dimensional plane of the membrane, but in liquid phase bilayers the molecules diffuse freely within this plane. Thus, in a liquid bilayer a given lipid will rapidly exchange locations with its neighbor millions of times a second and will, through the process of a random walk, migrate over long distances.
In membrane biology, fusion is the process by which two initially distinct lipid bilayers merge their hydrophobic cores, resulting in one interconnected structure. If this fusion proceeds completely through both leaflets of both bilayers, an aqueous bridge is formed and the internal contents of the two structures can mix. Alternatively, if only one leaflet from each bilayer is involved in the fusion process, the bilayers are said to be hemifused. In hemifusion, the lipid constituents of the outer leaflet of the two bilayers can mix, but the inner leaflets remain distinct. The aqueous contents enclosed by each bilayer also remain separated.
Cell surface receptors are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving extracellular molecules. They are specialized integral membrane proteins that allow communication between the cell and the extracellular space. The extracellular molecules may be hormones, neurotransmitters, cytokines, growth factors, cell adhesion molecules, or nutrients; they react with the receptor to induce changes in the metabolism and activity of a cell. In the process of signal transduction, ligand binding affects a cascading chemical change through the cell membrane.
The cell membrane is a biological membrane that separates and protects the interior of a cell from the outside environment. The cell membrane consists of a lipid bilayer, made up of two layers of phospholipids with cholesterols interspersed between them, maintaining appropriate membrane fluidity at various temperatures. The membrane also contains membrane proteins, including integral proteins that span the membrane and serve as membrane transporters, and peripheral proteins that loosely attach to the outer (peripheral) side of the cell membrane, acting as enzymes to facilitate interaction with the cell's environment. Glycolipids embedded in the outer lipid layer serve a similar purpose. The cell membrane controls the movement of substances in and out of a cell, being selectively permeable to ions and organic molecules. In addition, cell membranes are involved in a variety of cellular processes such as cell adhesion, ion conductivity, and cell signalling and serve as the attachment surface for several extracellular structures, including the cell wall and the carbohydrate layer called the glycocalyx, as well as the intracellular network of protein fibers called the cytoskeleton. In the field of synthetic biology, cell membranes can be artificially reassembled.
The anion exchanger family is a member of the large APC superfamily of secondary carriers. Members of the AE family are generally responsible for the transport of anions across cellular barriers, although their functions may vary. All of them exchange bicarbonate. Characterized protein members of the AE family are found in plants, animals, insects and yeast. Uncharacterized AE homologues may be present in bacteria. Animal AE proteins consist of homodimeric complexes of integral membrane proteins that vary in size from about 900 amino acyl residues to about 1250 residues. Their N-terminal hydrophilic domains may interact with cytoskeletal proteins and therefore play a cell structural role. Some of the currently characterized members of the AE family can be found in the Transporter Classification Database.