Membrane lipids asymmetric distribution

The average human red cell plasma membrane is lipid-rich with 240 million PL molecules, 190 million cholesterol molecules, 12 million glyco-lipid molecules and only 4 million protein molecules (Lux and Glader, 1981). The PLs of the red cell plasma membrane are asymmetrically distributed in the bilayer. The choline-containing PLs, PC and sphingomyelin represent 40% and 15%, respectively, of the total PL, and are enriched in the outer leaflet. In contrast, the amino PLs, PE and phospha-tidylserine (PS) are exclusively confined to the inner leaflet and constitute 35% and 15%, respectively, of total PLs. 

Binding of antibodies onto the thylakoid membrane VI. Asymmetric distribution of lipids and proteins in the thylakoid membrane Z. Naturforsch. 35c, 1024-1031... 

At a more molecular level, the influences of the composition of the membrane domains, which are characteristic of a polarized cell, on diffusion are not specifically defined. These compositional effects include the differential distribution of molecular charges in the membrane domains and between the leaflets of the membrane lipid bilayer (Fig. 3). The membrane domains often have physical differences in surface area, especially in the surface area that is accessible for participation in transport. For example, the surface area in some cells is increased by the presence of membrane folds such as microvilli (see Figs. 2 and 6). The membrane domains also have differences in metabolic selectivity and capacity as well as in active transport due to the asymmetrical distribution of receptors and transporters. 

Myelin in situ has a water content of about 40%. The dry mass of both CNS and PNS myelin is characterized by a high proportion of lipid (70-85%) and, consequently, a low proportion of protein (15-30%). By comparison, most biological membranes have a higher ratio of proteins to lipids. The currently accepted view of membrane structure is that of a lipid bilayer with integral membrane proteins embedded in the bilayer and other extrinsic proteins attached to one surface or the other by weaker linkages. Proteins and lipids are asymmetrically distributed in this bilayer, with only partial asymmetry of the lipids. The proposed molecular architecture of the layered membranes of compact myelin fits such a concept (Fig. 4-11). Models of compact myelin are based on data from electron microscopy, immunostaining, X-ray diffraction, surface probes studies, structural abnormalities in mutant mice, correlations between structure and composition in various species, and predictions of protein structure from sequencing information [4]. 

While examples such as these provide evidence that strong interactions of negatively-charged membrane lipids with membrane proteins the role in maintaining asymmetric distributions of lipids aaoss biological membranes is unclear. In any event such effects are likely to be of minor importance relative to actively mediated phospholipid translocation processes. 

The concept of a specific orientation for integral membrane proteins is quite general. All integral membrane proteins show such an asymmetry. This, coupled with the asymmetric distribution of lipids in the two leaflets, provides the two leaflets with different characteristics. 

Plasma membrane lipids are asymmetrically distributed between the two monolayers of the bilayer, although the asymmetry, unlike that of membrane proteins, is not absolute. In the plasma membrane of the erythrocyte, for example, choline-containing lipids (phosphatidylcholine and sphingomyelin) are typically found in the outer (extracellular or exoplasmic) leaflet (Fig. 11-5), whereas phosphatidylserine, phosphatidyl-ethanolamine, and the phosphatidylinositols are much more common in the inner (cytoplasmic) leaflet. Changes in the distribution of lipids between plasma membrane leaflets have biological consequences. For example, only when the phosphatidylserine in the plasma membrane moves into the outer leaflet is a platelet able to play its role in formation of a blood clot. For many other cells types, phosphatidylserine exposure on the outer surface marks a cell for destruction by programmed cell death. 

Lipids also show asymmetrical distributions between the inner and outer leaflets of the bilayer. In the erythrocyte plasma membrane, most of the phosphatidylethanolamine and phosphatidylserine are in the inner leaflet, whereas the phosphatidylcholine and sphingomyelin are located mainly in the outer leaflet. A similar asymmetry is seen even in artificial liposomes prepared from mixtures of phospholipids. In liposomes containing a mixture of phosphatidylethanolamine and phosphatidylcholine, phosphatidylethanolamine localizes preferentially in the inner leaflet, and phosphatidylcholine in the outer. For the most part, the asymmetrical distributions of lipids probably reflect packing forces determined by the different curvatures of the inner and outer surfaces of the bilayer. By contrast, the disposition of membrane proteins reflects the mechanism of protein synthesis and insertion into the membrane. We return to this topic in chapter 29. 

The ability to measure the distribution of lipids across natural biomembranes is a potentially powerful capability. Natural biomembranes maintain an asymmetric distribution of lipid components across the membrane with the inner leaflet rich in anionic lipids and both leaflets containing proteins and species specific to each... 

In the plasma membrane of animals (1), the amount of cholesterol is usually around 20-30 mol%. The rest of the lipids are mainly PC, PE, and sphingomyelin (SM) lipids, with smaller amounts of PS, PI, and glycolipids. These lipids are distributed asymmetrically across the membrane, because most cholesterol, PC, and glycolipids are located in the extracellular (outer) leaflet, whereas PS and PE lipids are located mainly in the intracellular (inner) monolayer. The lipid composition can be highly different in other organelles, however, as is the case in mitochondria (1), in which the mitochondrial membrane is composed of two (inner and outer) membranes. There, the amounts of cholesterol, SM, and PS are negligible most lipids are PC and PE. The major difference compared with plasma membrane is the concentration of cardiolipins. They are actually found only in bacterial and in mitochondrial membranes, where their numbers are significant even in mitochondria they are located mainly on the iimer membrane. 

Membrane proteins have a unique orientation because they are synthesized and inserted into the membrane in an asymmetric manner. This absolute asymmetry is preserved because membrane proteins do not rotate from one side of the membrane to the other and because membranes are always synthesized by the growth of preexisting membranes. Lipids, too, are asymmetrically distributed as a consequence of their mode of biosynthesis, but this asymmetry is usually not absolute, except for glycolipids. In the red-blood-cell membrane, sphingomyelin and phosphatidyl choline are preferentially located in the outer leaflet of the bilayer, whereas phosphatidyl ethanolamine and phosphatidyl serine are located mainly in the inner leaflet. Large amounts of cholesterol are present in both leaflets. 

Asymmetry in the lipid distribution over the bilayer could also be controlled in a similar way by the lateral packing pressure, which is likely to differ between constituent monolayers, due to the distinct chemical environments inside and outside the membrane. The enzymes involved may also be distributed asymmetrically. A configuration with constant, but nonzero, mean curvature, shown in Fig. 5.7, reflects such a situation. A membrane-spatming protein can then be viewed as a sensor of the lateral packing pressure in both monolayers. This speculation has some experimental justification. In a recent study of chromaffin granules, trans-membrane lipid asymmetry was shown to be induced by an ATP-dependent "flippase" [35]. 

With bilayer lipid membranes it is not possible to achieve a fully asymmetric arrangement of head groups or chains. There is no apparent reason why all the molecules of two independent layers should only concentrate in one layer. Nevertheless, a little asymmetric distribution is found in vesicles made of lipid mixtures. Cerebroside sulfate, an anionic monoglycosyl ceramide was, for example, added exclusively to the outer surface of a performed DPPC vesicle (see Scheme 2.2) which was quantitized by the metachromatic effect of acridine orange. 

TeWe, E., Astumian, R.D., Friauf, W.A., and Chock, P.B. (2001) Asymmetric pore distribution and loss of membrane lipid in electroporated DO PC vesicles. Biophysical Journal, 81 (2), 960-968. 

The membrane constituents are lipids (phospholipids, glycosphingolipids, and cholesterol Figure 10-5), carbohydrates, and proteins. The ratio of protein lipid carbohydrate on a weight basis varies considerably from membrane to membrane. For example, the human erythrocyte membrane has a ratio of about 49 43 8, whereas myelin has a ratio of 18 79 3. The composition of the normal human erythrocyte membrane is shown in Table 10-2. All membrane lipids are amphipathic (i.e., polar lipids). The polar heads of the phospholipids may be neutral, anionic, or dipolar. The surface of the membrane bears a net negative charge. The distribution of lipid constituents in the bilayer is asymmetrical. For example, in the erythrocyte membrane, phosphatidylethanolamine and phosphatidylserine are located primarily in the internal monolayer, whereas phosphatidylcholine and sphingomyelin are located in the external monolayer. 

Carbohydrate residues are covalently linked (exclusively on the external side of the bilayer) to proteins or lipids to form glycoproteins or glycolipids, respectively, both of which are asymmetrically distributed in the lipid bilayer (Figure 10-7). Fluidity of the membrane structure is determined by the degree of unsaturation of the hydrocarbon chains of the phospholipids and by the amount of cholesterol in the membrane. Hydrocarbon chains... 

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