All Transmembrane Proteins and Glycolipids Are Asymmetrically Oriented in the Bilayer

Every type of transmembrane protein has a specific orientation, known as its topology, with respect to the membrane faces. Its cytosolic segments always face the cytosol, and its exoplasmic segments always face the opposite side of the membrane. This asymmetry in protein orientation gives the two membrane faces their different properties. The orientations of different types of transmembrane proteins are established during their synthesis, as we will see in Chapter 13. Membrane proteins have never been observed to flip-flop across a membrane; such movement, requiring a transient movement of hydrophilic amino acid residues through the hydrophobic interior of the membrane, would be energetically unfavorable. Accordingly, the asymmetric topology of a transmembrane protein is maintained throughout the protein’s lifetime. As Figure 7-6 shows, membrane proteins retain their asymmetric orientation during membrane budding and fusion events; the same segment always faces the cytosol and the same segment is always exposed to the exoplasmic face. In multipass membrane proteins, the orientation of individual transmembrane segments can be affected by changes in the membrane’s phospholipid composition.

Many transmembrane proteins contain carbohydrate chains covalently linked to serine, threonine, or asparagine side chains of the polypeptide. Such transmembrane glycoproteins are always oriented so that all the carbohydrate chains are in the exoplasmic domain (see Figure 7-14 for the example of glycophorin A). Likewise, glycolipids, in which a carbohydrate chain is attached to the glycerol or sphingosine backbone of a membrane lipid, are always located in the exoplasmic leaflet, with the carbohydrate chain protruding from the membrane surface. The biosynthetic basis for the asymmetric glycosylation of proteins is described in Chapter 14. Both glycoproteins and glycolipids are especially abundant in the plasma membranes of eukaryotic cells and in the membranes of the intracellular compartments that establish the secretory and endocytic pathways; they are absent from the inner mitochondrial membrane, chloroplast lamellae, and several other intracellular membranes. Because the carbohydrate chains of glycoproteins and glycolipids in the plasma membrane extend into the extracellular space, they are available to interact with components of the extracellular matrix as well as with lectins (proteins that bind specific sugars), growth factors, and antibodies.

One important consequence of interactions involving membrane glycoproteins and glycolipids is illustrated by the ABO blood-group antigens. These three structurally related oligosaccharide components of certain glycoproteins and glycolipids are expressed on the surfaces of human red blood cells and many other cell types (Figure 7-20). All humans have the enzymes for synthesizing O antigen. Persons with type A blood also have a glycosyltransferase enzyme that adds an extra modified monosaccharide called N-acetylgalactosamine to O antigen to form A antigen. Those with type B blood have a different transferase that adds an extra galactose to O antigen to form B antigen. People with both transferases produce both A and B antigen (AB blood type); those who lack these transferases produce O antigen only (O blood type).

FIGURE 7-20 Human ABO blood group antigens. These antigens are oligosaccharide chains covalently attached to glycolipids or glycoproteins in the plasma membrane. The terminal oligosaccharide sugars distinguish the three antigens. The presence or absence of the glycosyltransferases that add galactose (Gal) or N-acetylgalactosamine (GalNAc) to O antigen determine a person’s blood type.

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People whose erythrocytes lack the A antigen, the B antigen, or both on their surface normally have antibodies against the missing antigen(s) in their serum. Thus if a type A or O person receives a transfusion of type B blood, antibodies against the B antigen will bind to the introduced red cells and trigger their destruction. To prevent such harmful reactions, blood group typing and appropriate matching of blood donors and recipients are required in all transfusions (Table 7-2).