All Transmembrane Proteins and Glycolipids Are Asymmetrically Oriented in the Bilayer

Lipid-anchored proteins are just one example of membrane proteins that are asymmetrically located with respect to the faces of cellular membranes. Each type of transmembrane protein also has a specific orientation with respect to the membrane faces. In particular, the same part(s) of a particular protein always faces the cytosol, whereas other parts face the exoplasmic space. This asymmetry in protein orientation confers different properties on the two membrane faces. (We describe how the orientation of different types of transmembrane proteins is established during their synthesis in Chapter 16.) 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 asymmetry of a transmembrane protein, which is established during its biosynthesis and insertion into a membrane, is maintained throughout the protein's lifetime.

Many transmembrane proteins contain carbohydrate chains covalently linked to serine, threonine, or asparagine side chains of the polypeptide. Such transmembrane glyco-proteins are always oriented so that the carbohydrate chains are in the exoplasmic domain (see Figures 5-11 and 5-12). Likewise, glycolipids, in which a carbohydrate chain is attached to the glycerol or sphingosine backbone, are always located in the exoplasmic leaflet with the carbohydrate chain protruding from the membrane surface. Both glycoproteins and glycolipids are especially abundant in the plasma membranes of eukaryotic cells; they are absent from the inner mi-tochondrial 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 lectins, growth factors, and antibodies.

HOne important consequence of such interactions is illustrated by the A, B, and O blood-group antigens. These three structurally related oligo-saccharide components of certain glycoproteins and gly-colipids are expressed on the surfaces of human erythrocytes and many other cell types (Figure 5-16). All humans have the enzymes for synthesizing O antigen. Persons with type A blood also have a glycosyltransferase that adds an extra

Lipid or protein

GlcNAcW Gal WGalNAc) A antigen

Lipid or protein

Lipid or protein

Lipid or protein

Lipid or protein

GlcNAcW Gal WGalNAc) A antigen

O antigen

B antigen

Glc = Glucose Gal = Galactose

GlcNAc = N-Acetylglucosamine GalNAc = N-Acetylgalactosamine Fuc = Fucose

O antigen

Lipid or protein

B antigen

Glc = Glucose Gal = Galactose

GlcNAc = N-Acetylglucosamine GalNAc = N-Acetylgalactosamine Fuc = Fucose

▲ FIGURE 5-16 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 ^-acetylgalactosamine (GalNAc) to O antigen determine a person's blood type.

^-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).

Persons whose erythrocytes lack the A antigen, 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 epitope 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 5-2). I

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