Biological Membranes Are Asymmetrical

Although phospholipids diffuse laterally in the plane of the bilayer and rotate more or less freely about an axis perpendicular to this plane, movements from one side of the bilayer to the other are a different matter. Diffusion across the membrane, a transverse, or flip-flop, motion, requires getting the polar head-group of the phospholipid through the 

Glycophorin is one of the numerous glycoproteins found in the plasma membranes of erythrocytes and other cells. These proteins provide good illustrations of membrane structural asymmetry, because the oligosaccharides 

Topography of glycophorin in the mammalian erythrocyte membrane. Carbohydrate residues (small blue hexagons) are attached to the hydroxyl groups of threonine and serine residues in the N-terminal domain of the protein. The N-terminus and all of the carbohydrates are outside the cell the C-terminal domain of the protein is inside. The hydrophobic, membrane-spanning domain is flanked by charged amino acid residues that may interact electrostatically with the polar head-groups of the phospholipids. 

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. 

Volume 5, 1976 by Annual Reviews, Inc.) (Bottom) Molecular interpretation of the heat-absorbing reaction during the phase transition. 

---

Biological membranes are asymmetric structures. There are several kinds of asymmetry to consider. Both the lipids and the proteins of membranes exhibit lateral and transverse asymmetries. Lateral asymmetry arises when lipids or proteins of particular types cluster in the plane of the membrane. 

Biological Membranes Are Asymmetrical form bilayers with the hydrophilic groups exposed. 

Biological membranes are asymmetric. Consistent with this asymmetry, a protein that has been inserted into a membrane in a particular orientation usually retains that orientation indefinitely. 

Asymmetry. Biological membranes are asymmetric that is, the lipid composition of each half of a bilayer is different. For example, the human red blood cell membrane possesses substantially more phosphatidylcholine and sphingomyelin on its outside surface. Most of the membrane s phosphatidylserine and phos-phatidylethanolamine are on the inner side. Membrane asymmetry is not unexpected, because each side of a membrane is exposed to a different environment. Asymmetry originates during membrane synthesis, because phospholipid biosynthesis occurs on only one side of a membrane (Special Interest Box 12.3). The protein components of membranes (discussed below) also exhibit considerable asymmetry with distinctly different functional domains within membrane and on the cytoplasmic and extracellular faces of membrane. 

As early as 1972, it was known that many biological membranes are asymmetric with respect to distribution of phospholipids between the inner and outer leaflets of the bilayer. Once such asymmetry is established, what factors act to preserve it ... 

The glycerolipids are distributed in individual membranes at characteristic ratios. There is also good evidence that biological membranes are asymmetric with regard to their lipid as well as their protein distribution. There may also be some lateral heterogeneity with particular regions of the membrane being enriched with certain lipids. 

Membranes are asymmetric. The two faces of biological membranes always differ from each other. 

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. 

Our present ideas about the nature of biological membranes, which are so fundamental to all biochemical processes, are based on the Singer-Nicholson mosaic model. This model of the membrane is based on a phospholipid bilayer that is, however, asymmetrical. In the outside monolayer, phosphatidylcholine (lecithin) predominates, whereas the inner monolayer on the cytoplasmic side is rich in a mixture of phos-phatidylethanolamine, phosphatidylserine, and phosphatidylinositol. Cholesterol molecules are also inserted into the bilayer, with their 3-hydroxyl group pointed toward the aqueous side. The hydrophobic fatty acid tails and the steran skeleton of cholesterol... 

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. 

Membranes are structurally and functionally asymmetric. The outer and inner surfaces of all known biological membranes have different components and different enzymatic activities. A clear-cut example is the pump that regulates the concentration of Na+ and K+ ions in cells (Figure 12.34). This transport protein is located in the plasma membrane of nearly all cells in higher organisms. The Na+-K+ pump is oriented so that it pumps Na+ out of the cell and K+ into it. Furthermore, ATP must be on the inside of the cell to drive the pump. Ouabain, a specific inhibitor of the pump, is effective only if it is located outside. 

---