The topology of a membrane protein refers to the number of times its polypeptide chain spans the membrane and the orientation of those membrane-spanning segments within the membrane. The key elements of a protein that determine its topology are the membrane-spanning segments themselves, which are usually α helices containing 20–25 hydrophobic amino acids that contribute to energetically favorable inter actions within the hydrophobic interior of the phospholipid bilayer.
Most integral membrane proteins fall into one of the five topological classes illustrated in Figure 1. Topological classes I, II, III, and the tail-anchored proteins are single pass membrane proteins, which have only one membrane spanning α-helical segment. Type I proteins have a cleaved N-terminal ER signal sequence and are anchored in the membrane with their hydrophilic N-terminal region on the luminal face (also known as the exoplasmic face) and their hydrophilic C-terminal region on the cytosolic face. Type II proteins do not contain a cleavable ER signal sequence and are oriented with their hydrophilic N-terminal region on the cytosolic face and their hydrophilic C-terminal region on the exoplasmic face (i.e., opposite to type I proteins). Type III proteins have a hydrophobic membrane-spanning segment at their N-terminus and thus have the same orientation as type I proteins, but do not contain a cleavable signal sequence. Finally, tail-anchored proteins have a hydrophobic segment at their C-terminus that spans the membrane. These different topologies reflect distinct mechanisms used by the cell to establish the orientation of transmembrane segments, as we will see shortly.
The proteins forming topological class IV contain two or more membrane-spanning segments and are sometimes called multipass membrane proteins. For example, many of the membrane transport proteins discussed in Chapter 11 and the numerous G protein–coupled receptors covered in Chapter 15 belong to this class.
Some lipid-anchored membrane proteins are also synthesized on the ER. These membrane proteins lack a hydrophobic membrane-spanning segment altogether; instead, they are linked to an amphipathic phospholipid anchor that is embedded in the membrane (Figure 1, right).
Fig1. Classes of ER membrane proteins. Five topological classes of integral membrane proteins are synthesized on the rough ER, as is a sixth type tethered to the membrane by a phospholipid anchor. These membrane proteins are classified by their orientation in the membrane and the types of signals they contain to direct them there. In the integral membrane proteins, hydrophobic segments of the protein chain form α helices embedded in the membrane bilayer; the regions outside the membrane are hydrophilic and fold into various conformations. All type IV proteins have multiple transmembrane α helices. The type IV topology depicted here corresponds to that of G protein–coupled receptors: seven α helices, the N-terminus on the exoplasmic side of the membrane, and the C-terminus on the cytosolic side. Other type IV proteins may have a different number of helices and various orientations of the N-terminus and C-terminus. See E. Hartmann et al., 1989, P. Natl. Acad. Sci. USA 86:5786, and C. A. Brown and S. D. Black, 1989, J. Biol. Chem. 264:4442.
