Membrane bilayer lipid distribution across

Bidirectional transporters. The bidirectional transporters at the plasma membrane randomize the lipid distribution across the plane of the bilayer, and are commonly referred to as scramblases [17]. The action of scramblase is summarized in Fig. 5, and is similar to that of the previously described transbilayer transporter present in the ER. Scramblase protein was first functionally identified in erythrocytes but is also present in nucleated cells. The scramblase shows no lipid specificity and essentially collapses the asymmetry of lipids at the cell surface. Phospholipids, SM, and glycosphingolipids all serve as substrates. The randomizing function of the plasma membrane protein is activated by Ca " and does not require ATP. 

Proteins that can flip phospholipids from one side of a bilayer to the other have also been identified in several tissues (Figure 9.11). Called flippases, these proteins reduce the half-time for phospholipid movement across a membrane from 10 days or more to a few minutes or less. Some of these systems may operate passively, with no required input of energy, but passive transport alone cannot establish or maintain asymmetric transverse lipid distributions. However, rapid phospholipid movement from one monolayer to the other occurs in an ATP-dependent manner in erythrocytes. Energy-dependent lipid flippase activity may be responsible for the creation and maintenance of transverse lipid asymmetries. 

The properties of membranes commonly studied by fluorescence techniques include motional, structural, and organizational aspects. Motional aspects include the rate of motion of fatty acyl chains, the head-group region of the phospholipids, and other lipid components and membrane proteins. The structural aspects of membranes would cover the orientational aspects of the lipid components. Organizational aspects include the distribution of lipids both laterally, in the plane of the membrane (e.g., phase separations), and across the membrane bilayer (phospholipid asymmetry) and distances from the surface or depth in the bilayer. Finally, there are properties of membranes pertaining to the surface such as the surface charge and dielectric properties. Fluorescence techniques have been widely used in the studies of membranes mainly since the time scale of the fluorescence lifetime coincides with the time scale of interest for lipid motion and since there are a wide number of fluorescence probes available which can be used to yield very specific information on membrane properties. 

Figure 2.6. The role of lipid membranes in drag distribution, a Structure of phosphatidylcholine (left), and schematic of a lipid bilayer (right). The hydrophobic interior phase represents the kinetic barrier to drag absorption and distribution. b Drag diffusion across lipid bilayers. Partition into the bilayer is the rate-limiting step. Hydrophilic drag molecules (left) will not efficiently partition into the hydrophobic phase and therefore can t get across the membrane easily. In contrast, hydrophobic molecules (right) will enter the membrane readily and therefore will cross the membrane more efficiently.

A characteristic of all membranes is an asymmetry in lipid composition across the bilayer. Although most phospholipids are present in both membrane leaflets, they are commonly more abundant in one or the other leaflet. For instance, in plasma membranes from human erythrocytes and certain canine kidney cells grown in culture, almost all the sphingomyelin and phosphatidylcholine, both of which form less fluid bilayers, are found in the exoplasmic leaflet. In contrast, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol, which form more fluid bilayers, are preferentially located in the cytosolic leaflet. This segregation of lipids across the bilayer may influence membrane curvature (see Figure 5-8c). Unlike phospholipids, cholesterol is relatively evenly distributed in both leaflets of cellular membranes. 

Our present view of the cell membrane structure is that it is analogous to a two-dimensional oriented solution of globular lipoproteins dispersed in a discontinuous fluid bilayer of lipid solvent [2]. Phospholipids constitute the bulk of the lipids. Both components of the membrane (proteins and lipid) are free to some degree to have lateral mobility in the plane of the membrane and in some cases are asymmetrically distributed across the two halves of the bilayer [2]. Some proteins are peripherally attached to either of the two faces while other polypeptide chains may span the whole thickness of the membrane [2]. These latter proteins probably correspond to... 

The membranes of cells are generally asymmetric, in that the lipids and proteins that inhabit the membrane are not evenly distributed across both the leaflets of the bilayer. To maintain this necessary membrane asymmetry, transverse diffusion of phospholipids (flip-flop. Figure 6a) in cellular membranes is accelerated by translocase enzymes like the flippases. These enzymes overcome the energy barrier for the passage of polar headgroups through the apolar center of the membrane and maintain asymmetry by the consumption of adenosine triphosphate (ATP). ... 

A notable feature of the lipid regions of biological membranes is that the different phospholipid types may be asymmetrically distributed across the bilayer. For the erythrocyte membrane for example, it has been demonstrated by surface labelling and phospholipase digestion that the sphingomyelin and phosphatidylcholine are located in the outer half of the bilayer, whereas the phosphatidylethanolamine and phosphatidylserine are localized to the inner half (Zwaal et al., 1973). 

Of course there are many phenomena that equilibrate on the nanosecond timescale. However, the majority of relevant events take much more time. For example, the ns timescale is much too short to allow for the self-assembly of a set of lipids from a homogeneously distributed state to a lamellar topology. This is the reason why it is necessary to start a simulation as close as possible to the expected equilibrated state. Of course, this is a tricky practice and should be considered as one of the inherent problems of MD. Only recently, this issue was addressed by Marrink [56]. Here the homogeneous state of the lipids was used as the start configuration, and at the end of the simulation an intact bilayer was found. Permeation, transport across a bilayer, and partitioning of molecules from the water to the membrane phase typically take also more time than can be dealt with by MD. We will return to this point below. 

The cell plasma membrane consists of a variety of proteins associated with the lipid bilayer and they perform multitasks in cell function. The control of transport of ions and molecules across membrane is accomplished through specialized function of membrane proteins. These proteins are distributed in membrane on the outer surface, some on the inner surface, and some others are transmembrane proteins with external and cytoplasmic domains. The majority of the transmembrane proteins are the ion channels or signaling proteins. Generally, hpid to protein ratio is 60 40 but this ratio is found variable in different cells and types of membranes. Membrane proteins impart the dynamic structure and selectivity to membrane function. Both proteins and hpids show motional and diffusion properties within the bUayer structure. 

Lipid transfer proteins have proved to be a useful tool for studying artificial and natural membranes (for a recent review see Bloj and Zilver-smit, 1981a). With the ability of phospholipid transfer proteins to replace selectively the phospholipid molecules on the exposed surfaces of membranes, information about the asymmetric distribution of phospholipids across a bilayer and the rate of transbilayer movement of phospholipid... 

Of what practical value is the process of diffusion to the cell Certainly, diffusion is able to distribute metabolites effectively throughout the interior of the cell. But what about the movement of molecules through the membrane Because of the lipid bilayer structure of the membrane, only a few molecules are able to diffuse freely across a membrane. These include small molecules such as O2 and CO2. Any large or highly charged molecules or ions are not able to pass through the lipid bilayer directly. Such molecules require an assist from cell membrane proteins. Any membrane that allows the diffusion of some molecules but not others is said to be selectively ipermeahle. 

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