Insertion of Proteins into the ER Membrane

In previous chapters we have encountered many of the vast array of integral (transmembrane) proteins that are present in the plasma membrane and other cellular membranes. Each such protein has a unique orientation with respect to the membrane's phospholipid bilayer. Integral proteins located in ER, Golgi, and lysosomal membranes and in the plasma membrane, which are synthesized on the rough ER, remain embedded in the membrane as they move to their final destinations along the same pathway followed by soluble secretory proteins (see Figure 16-1). During this transport, the orientation of a membrane protein is preserved; that is, the same segments of the protein always face the cytosol, while other segments always face in the opposite direction. Thus the final orientation of these membrane proteins is established during their biosynthesis on the ER membrane. In this section, we first see how integral proteins can interact with membranes. Then we examine how several types of sequences, collectively known as topogenic sequences, direct the insertion and orientation of various classes of integral proteins into the membrane. These processes build on and adapt the basic mechanism used to translocate soluble secretory proteins across the ER membrane.

Several Topological Classes of Integral Membrane Proteins Are Synthesized on the ER

The topology of a membrane protein refers to the number of times that its polypeptide chain spans the membrane and the orientation of these membrane-spanning segments within the membrane. The key elements of a protein that determine its topology are membrane-spanning segments themselves, which usually contain 20-25 hydrophobic amino acids. Each such segment forms an a helix that spans the membrane, with the hydrophobic amino acid residues anchored to the hydrophobic interior of the phospholipid bilayer.

Scientists have found it useful to categorize integral membrane proteins into the four topological classes illustrated in Figure 16-10. Topological classes I, II, and III comprise single-pass proteins, which have only one membrane-spanning a-helical segment. Type I proteins have a cleaved N-terminal 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 signal sequence and are oriented with their hydrophilic N-terminal region on the cy-tosolic face and their hydrophilic C-terminal region on the exoplasmic face (i.e., opposite to type I proteins). Type III proteins have the same orientation as type I proteins, but do not contain a cleavable signal sequence. These different topologies reflect distinct mechanisms used by the cell to

COO-

Cytosol

Exoplasmic space

(ER or Golgi lumen;

cell exterior)

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Cytosol

Exoplasmic space

(ER or Golgi lumen;

cell exterior)

Cleaved signal sequence

Type I

Glycophorin LDL receptor Influenza HA protein Insulin receptor Growth hormone receptor

Cleaved signal sequence

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