A Phospholipid Anchor Tethers Some Cell-Surface Proteins to the Membrane
Some cell-surface proteins are anchored to the phospholipid bilayer not by a sequence of hydrophobic amino acids, but by a covalently attached amphipathic molecule, glycosylphosphatidylinositol (GPI) (Figure 13-15a; see also Chapter 7). These proteins are synthesized and initially anchored to the ER membrane exactly like type I transmembrane proteins, with a cleaved N-terminal signal sequence and an internal stop-transfer anchor sequence directing the process (see Figure 13-11). However, a short sequence of amino acids in the luminal domain, adjacent to the membrane-spanning domain, is recognized by a transamidase located within the ER membrane. This enzyme simultaneously cleaves off the original stop-transfer anchor sequence and transfers the luminal portion of the protein to a preformed GPI anchor in the membrane (Figure 13-15b).
FIGURE 13-15 GPI-anchored proteins. (a) Structure of a glycosylphosphatidylinositol (GPI) molecule from yeast. The hydrophobic portion of the molecule is composed of fatty acyl chains, whereas the polar (hydrophilic) portion is composed of carbohydrate residues and phosphate groups. In other organisms, both the length of the acyl chains and the carbohydrate moieties may vary somewhat from the structure shown. (b) Formation of GPI-anchored proteins in the ER membrane. The protein is synthesized and initially inserted into the ER membrane like a type I transmembrane protein, as shown in Figure 13-11. A specific transamidase simultaneously cleaves the precursor protein within the exoplasmic-facing domain, near the stop-transfer anchor sequence (red), and transfers the carboxyl group of the new C-terminus to the terminal amino group of a preformed GPI anchor. See C. Abeijon and C. B. Hirschberg, 1992, Trends Biochem. Sci. 17:32, and K. Kodukula et al., 1992, P. Natl. Acad. Sci. USA 89:4982.
Why change one type of membrane anchor for another? Attachment of the GPI anchor, which results in removal of the cytosol-facing hydrophilic domain from the protein, can have several consequences. Proteins with GPI anchors, for example, can diffuse relatively rapidly in the plane of the phospholipid bilayer. In contrast, many proteins anchored by membrane-spanning α helices are impeded from moving laterally in the membrane because their cytosol-facing segments interact with the cytoskeleton. In addition, the GPI anchor targets the attached protein to the apical domain of the plasma membrane (instead of the basolateral domain) in certain polarized epithelial cells, as we discuss in Chapter 14.