Flippase

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Structure of a flippase, showing the two major subunits of the enzyme. Flippase pglK pdb 5c73.png
Structure of a flippase, showing the two major subunits of the enzyme.

Flippases are transmembrane lipid transporter proteins located in the cell membrane. They are responsible for aiding the movement of phospholipid molecules between the two layers, or leaflets, that compose the membrane (transverse diffusion, also known as a "flip-flop" transition). Flippases move lipids to the cytosolic layer, usually from the extracellular layer. Floppases do the opposite, moving lipids to the extracellular layer. Both flippases and floppases are powered by ATP hydrolysis and are either P4-ATPases or ATP-Binding Cassette transporters. Scramblases are energy-independent and transport lipids in both directions. [1] [2] [3]

Contents

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. [4] 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. [4] 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.

Lateral and transverse movements of lipid. Lateral and transverse movements of lipid.jpg
Lateral and transverse movements of lipid.

Although Flip-Flop is slow, This movement is necessary to continue their normal function of growth and mobility. [5] The possibility of active maintenance of an asymmetric distribution of molecules in the phospholipid bilayer was predicted in the early 1970s by Mark Bretscher. [6]  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. [7] 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 [8] and as a signal for efferocytosis. [9]

Different classes of lipid transporters

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

Three major classes of lipid transporters and different functions to lipid of each enzyme. Classes of lipid tranpsorters.png
Three major classes of lipid transporters and different functions to lipid of each enzyme.
  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. [11] Flippases belong to P-type Flippase [10] and it moves lipids from the exoplasmic to the cytosolic face. [11]

Structure and domains of P4-type flippases

Domains of flippase. Domains of flippase.jpg
Domains of flippase.

P4-type flippase contains a large transmembrane segment and two major subunits, a catalytic domain called the alpha-subunit and an accessory domain named beta-subunit. [5] Transmembrane segments contain 10 transmembrane alpha helices and this domain together with beta-subunit plays important role in stability, localization and recognition of substrate (lipid) of flippase. [5] Alpha-subunits include A, P and N domains and each of them corresponds to a different function of flippase. A-domain is an actuator segment of flippase that facilitates phospholipid binding through conformational change of the complex, although it does not bind the phospholipid itself. P-domain is responsible for binding phosphate, a product of ATP hydrolysis. The next domain is N-domain, whose job is to bind to substrate (ATP). [5] Finally, a C-terminal autoregulatory domain has been identified, whose function differs between yeast and mammalian P4-type flippases. [12]

Mechanism of P4-type flippases

Schematic of flippase mechanism, EP stands for phosphorylated flippases. PL represents the substrate, which is phospholipid. Flippase mechanism.jpg
Schematic of flippase mechanism, EP stands for phosphorylated flippases. PL represents the substrate, which is phospholipid.

In order to bind specific lipid on the outer layer of membrane, P4-type flippase needs to be phosphorylated by ATP on its P-domain. After ATP hydrolysis and phosphorylation, P4-type flippases undergo conformational change from E1 to E2 (E1 and E2 stand for different conformations of flippases). [5] Further conformational change is induced by the binding of a phospholipid, resulting in the E2Pi.PL conformation. [12] The flippase in its E2 conformation can then be dephosphorylated at its P-domain, allowing the lipid to be transported to the inner layer of membrane, where it diffuses away from the flippase. As the phospholipid dissociates from the complex, a conformational change on flippase occurs from E2 back to E1 readying it for the next cycle of lipid transportation. [5]

The A-domain binds to the N-domain after that domain releases ADP. The A-domain can bind to the N-domain by a TGES four-amino-acid motif when the P-domain is phosphorylated. The release of ADP from the N-domain transitions the complex from the E1P-ADP state to the E2P state, which might be further stabilized by binding of the C-terminal regulatory domain. Binding of a phospholipid to the first two transmembrane segments induces a conformational change that rotates the A domain outward by 22 degrees, allowing dephosphorylation of the P domain. Dephosphorylation of the P-domain is energetically coupled to translocation of the polar phospholipid head across the membrane leaflets. [12]

See also

Related Research Articles

<span class="mw-page-title-main">Biological membrane</span> Enclosing or separating membrane in organisms acting as selective semi-permeable barrier

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.

<span class="mw-page-title-main">Facilitated diffusion</span> Biological process

Facilitated diffusion is the process of spontaneous passive transport of molecules or ions across a biological membrane via specific transmembrane integral proteins. Being passive, facilitated transport does not directly require chemical energy from ATP hydrolysis in the transport step itself; rather, molecules and ions move down their concentration gradient according to the principles of diffusion.

<span class="mw-page-title-main">Phospholipid</span> Class of lipids

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.

<span class="mw-page-title-main">ATPase</span> Dephosphorylation enzyme

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.

<span class="mw-page-title-main">Integral membrane protein</span> Type of membrane protein that is permanently attached to the biological membrane

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.

<span class="mw-page-title-main">Lipid bilayer</span> Membrane of two layers of lipid molecules

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.

<span class="mw-page-title-main">Peripheral membrane protein</span> Membrane proteins that adhere temporarily to membranes with which they are associated

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.

<span class="mw-page-title-main">Fluid mosaic model</span> Describe the fluid mosaic model of plasma membrane

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.

In cellular biology, membrane transport refers to the collection of mechanisms that regulate the passage of solutes such as ions and small molecules through biological membranes, which are lipid bilayers that contain proteins embedded in them. The regulation of passage through the membrane is due to selective membrane permeability – a characteristic of biological membranes which allows them to separate substances of distinct chemical nature. In other words, they can be permeable to certain substances but not to others.

<span class="mw-page-title-main">ABC transporter</span> Gene family

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.

<span class="mw-page-title-main">Glycerophospholipid</span> Class of lipids

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.

<span class="mw-page-title-main">Phospholipid scramblase</span> Protein

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.

<span class="mw-page-title-main">P-type ATPase</span>

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.

<span class="mw-page-title-main">Cell surface receptor</span> Class of ligand activated receptors localized in surface of plama cell membrane

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 thiol-activated Cholesterol-dependent Cytolysin(CDC) family is a member of the MACPF superfamily. Cholesterol dependent cytolysins are a family of β-barrel pore-forming exotoxins that are secreted by gram-positive bacteria. CDCs are secreted as water-soluble monomers of 50-70 kDa, that when bound to the target cell, form a circular homo-oligomeric complex containing as many as 40 monomers. Through multiple conformational changes, the β-barrel transmembrane structure is formed and inserted into the target cell membrane. The presence of cholesterol in the target membrane is required for pore formation, though the presence of cholesterol is not required by all CDCs for binding. For example, intermedilysin secreted by Streptococcus intermedius will bind only to target membranes containing a specific protein receptor, independent of the presence of cholesterol, but cholesterol is required by intermedilysin for pore formation. While the lipid environment of cholesterol in the membrane can affect toxin binding, the exact molecular mechanism that cholesterol regulates the cytolytic activity of the CDC is not fully understood.

<span class="mw-page-title-main">Cell membrane</span> Biological membrane that separates the interior of a cell from its outside environment

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 SecA protein is a cell membrane associated subunit of the bacterial Sec or Type II secretory pathway, a system which is responsible for the secretion of proteins through the cell membrane. Within this system the SecA ATPase forms a translocase complex with the SecYEG channel, thereby driving the movement of the protein substrate across the membrane.

<span class="mw-page-title-main">CDP-choline pathway</span>

The CDP-choline pathway, first identified by Eugene P. Kennedy in 1956, is the predominant mechanism by which mammalian cells synthesize phosphatidylcholine (PC) for incorporation into membranes or lipid-derived signalling molecules. The CDP-choline pathway represents one half of what is known as the Kennedy pathway. The other half is the CDP-ethanolamine pathway which is responsible for the biosynthesis of the phospholipid phosphatidylethanolamine (PE).

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.

References

  1. ↑ Maxfield, Frederick R.; Menon, Anant K. (2016), "Intramembrane and Intermembrane Lipid Transport", Biochemistry of Lipids, Lipoproteins and Membranes, Elsevier, pp. 415–436, doi:10.1016/b978-0-444-63438-2.00014-6, ISBN   978-0-444-63438-2 , retrieved 2024-06-04
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  4. 1 2 Pace, R. J.; Chan, Sunney I. (1982-04-15). "Molecular motions in lipid bilayers. III. Lateral and transverse diffusion in bilayers". The Journal of Chemical Physics. 76 (8): 4241–4247. Bibcode:1982JChPh..76.4241P. doi:10.1063/1.443501. ISSN   0021-9606.
  5. 1 2 3 4 5 6 Nagata, Shigekazu; Sakuragi, Takaharu; Segawa, Katsumori (February 2020). "Flippase and scramblase for phosphatidylserine exposure". Current Opinion in Immunology. 62: 31–38. doi: 10.1016/j.coi.2019.11.009 . PMID   31837595.
  6. ↑ Bretscher, Mark S. (March 1972). "Asymmetrical Lipid Bilayer Structure for Biological Membranes". Nature New Biology. 236 (61): 11–12. doi:10.1038/newbio236011a0. ISSN   0090-0028. PMID   4502419.
  7. ↑ Clarke, R.J.; Hossain, K.R.; Cao, K. (October 2020). "Physiological roles of transverse lipid asymmetry of animal membranes". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1862 (10): 183382. doi:10.1016/j.bbamem.2020.183382. PMID   32511979.
  8. ↑ Castegna, Alessandra; Lauderback, Christopher M; Mohmmad-Abdul, Hafiz; Butterfield, D.Allan (April 2004). "Modulation of phospholipid asymmetry in synaptosomal membranes by the lipid peroxidation products, 4-hydroxynonenal and acrolein: implications for Alzheimer's disease". Brain Research. 1004 (1–2): 193–197. doi:10.1016/j.brainres.2004.01.036. PMID   15033435.
  9. ↑ Nagata, Shigekazu; Segawa, Katsumori (February 2021). "Sensing and clearance of apoptotic cells". Current Opinion in Immunology. 68: 1–8. doi:10.1016/j.coi.2020.07.007. PMID   32853880.
  10. 1 2 Sharom, Frances J. (2011). "Flipping and flopping-lipids on the move". IUBMB Life. 63 (9): 736–746. doi:10.1002/iub.515. PMID   21793163.
  11. 1 2 Hankins, Hannah M.; Baldridge, Ryan D.; Xu, Peng; Graham, Todd R. (January 2015). "Role of Flippases, Scramblases and Transfer Proteins in Phosphatidylserine Subcellular Distribution". Traffic. 16 (1): 35–47. doi:10.1111/tra.12233. ISSN   1398-9219. PMC   4275391 . PMID   25284293.
  12. 1 2 3 Hiraizumi M, Yamashita K, Nishizawa T, Nureki O (2019). "Cryo-EM structures capture the transport cycle of the P4-ATPase flippase". Science. 365 (6458): 1149–1155. Bibcode:2019Sci...365.1149H. doi:10.1126/science.aay3353. PMID   31416931.
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