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.