Membrane Lipids Are Usually Distributed Unequally in the Exoplasmic and Cytosolic Leaflets

A characteristic of all membranes is an asymmetry in lipid composition across the bilayer. Although most phospho-lipids 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.

The relative abundance of a particular phospholipid in the two leaflets of a plasma membrane can be determined on the basis of its susceptibility to hydrolysis by phospho-lipases, enzymes that cleave various bonds in the hy-drophilic ends of phospholipids (Figure 5-9). Phospholipids in the cytosolic leaflet are resistant to hydrolysis by phos-pholipases added to the external medium because the enzymes cannot penetrate to the cytosolic face of the plasma membrane.

How the asymmetric distribution of phospholipids in membrane leaflets arises is still unclear. In pure bilayers, phospholipids do not spontaneously migrate, or flip-flop, from one leaflet to the other. Energetically, such flip-flopping is extremely unfavorable because it entails movement of the polar phospholipid head group through the hydrophobic interior of the membrane. To a first approximation, the asym-

Polar head group R O

Polar head group R O

(CH2)n CH3

(CH2)n CH3

▲ FIGURE 5-9 Specificity of phospholipases. Each type of phospholipase cleaves one of the susceptible bonds shown in red. The glycerol carbon atoms are indicated by small numbers. In intact cells, only phospholipids in the exoplasmic leaflet of the plasma membrane are cleaved by phospholipases in the surrounding medium. Phospholipase C, a cytosolic enzyme, cleaves certain phospholipids in the cytosolic leaflet of the plasma membrane.

metry in phospholipid distribution results from the vectorial synthesis of lipids in the endoplasmic reticulum and Golgi. Sphingomyelin is synthesized on the luminal (exoplasmic) face of the Golgi, which becomes the exoplasmic face of the plasma membrane. In contrast, phosphoglycerides are synthesized on the cytosolic face of the ER membrane, which is topologically identical with the cytosolic face of the plasma membrane (see Figure 5-4). Clearly, this explanation does not account for the preferential location of phosphatidyl-choline in the exoplasmic leaflet. Movement of this phos-phoglyceride and perhaps others from one leaflet to the other in some natural membranes is catalyzed by certain ATP-powered transport proteins called flippases discussed in Chapters 7 and 18.

The preferential location of lipids to one face of the bi-layer is necessary for a variety of membrane-based functions. For example, the head groups of all phosphorylated forms of phosphatidylinositol face the cytosol. Certain of them are cleaved by phospholipase C located in the cytosol; this enzyme in turn is activated as a result of cell stimulation by many hormones. These cleavages generate cytosol-soluble phosphoinositols and membrane-soluble diacylglycerol. As we see in later chapters, these molecules participate in intra-cellular signaling pathways that affect many aspects of cellular metabolism. Phosphatidylserine also is normally most abundant in the cytosolic leaflet of the plasma membrane. In the initial stages of platelet stimulation by serum, phos-phatidylserine is briefly translocated to the exoplasmic face, presumably by a flippase enzyme, where it activates enzymes participating in blood clotting.

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