Covalently Attached Hydrocarbon Chains Anchor Some Proteins to Membranes

In eukaryotic cells, several types of covalently attached lipids anchor some proteins to one or the other leaflet of the plasma membrane and certain other cellular membranes. In these lipid-anchored proteins, the lipid hydrocarbon chains are embedded in the bilayer, but the protein itself does not enter the bilayer.

A group of cytosolic proteins are anchored to the cytoso-lic face of a membrane by a fatty acyl group (e.g., myristate or palmitate) attached to the N-terminal glycine residue (Figure 5-15a). Retention of such proteins at the membrane by the N-terminal acyl anchor may play an important role in a membrane-associated function. For example, v-Src, a mutant form of a cellular tyrosine kinase, is oncogenic and can transform cells only when it has a myristylated N-terminus.

A second group of cytosolic proteins are anchored to membranes by an unsaturated fatty acyl group attached to a cysteine residue at or near the C-terminus (Figure 5-15b). In these proteins, a farnesyl or geranylgeranyl group is bound through a thioether bond to the —SH group of a C-terminal cysteine residue. These prenyl anchors are built from isoprene units (C5), which are also used in the synthesis of cholesterol (Chapter 18). In some cases, a second geranylgeranyl group or a palmitate group is linked to a nearby cysteine residue. The additional anchor is thought to reinforce the attachment of the protein to the membrane. Ras, a GTPase superfamily protein that functions in intracellular signaling, is localized to the cytosolic face of the plasma membrane by such a double anchor. Rab proteins, which also belong to the GTPase su-perfamily, are similarly bound to the cytosolic surface of in-tracellular vesicles by prenyl-type anchors; these proteins are required for the fusion of vesicles with their target membranes (Chapter 17).

Some cell-surface proteins and heavily glycosylated pro-teoglycans of the extracellular matrix are bound to the exo-

▲ FIGURE 5-15 Anchoring of plasma-membrane proteins to the bilayer by covalently linked hydrocarbon groups.

(a) Cytosolic proteins such as v-Src are associated with the plasma membrane through a single fatty acyl chain attached to the N-terminal glycine (Gly) residue of the polypeptide. Myristate (C14) and palmitate (C16) are common acyl anchors. (b) Other cytosolic proteins (e.g., Ras and Rab proteins) are anchored to the membrane by prenylation of one or two cysteine (Cys) residues, at or near the C-terminus. The anchors are farnesyl (C15) and geranylgeranyl (C20) groups, both of which are unsaturated. (c) The lipid anchor on the exoplasmic surface of the plasma membrane is glycosylphosphatidylinositol (GPI). The phosphatidylinositol part (red) of this anchor contains two fatty acyl chains that extend into the bilayer. The phosphoethanolamine unit (purple) in the anchor links it to the protein. The two green hexagons represent sugar units, which vary in number and arrangement in different GPI anchors. The complete structure of a yeast GPI anchor is shown in Figure 16-14. [Adapted from H. Sprong et al., 2001, Nature Rev. Mol. Cell Biol. 2:504.]

plasmic face of the plasma membrane by a third type of anchor group, glycosylphosphatidylinositol (GPI). The exact structures of GPI anchors vary greatly in different cell types, but they always contain phosphatidylinositol (PI), whose two fatty acyl chains extend into the lipid bilayer; phospho-ethanolamine, which covalently links the anchor to the C-terminus of a protein; and several sugar residues (Figure 5-15c). Various experiments have shown that the GPI anchor is both necessary and sufficient for binding proteins to the membrane. For instance, the enzyme phospholipase C cleaves the phosphate-glycerol bond in phospholipids and in GPI anchors (see Figure 5-9). Treatment of cells with phospholipase C releases GPI-anchored proteins such as Thy-1 and placental alkaline phosphatase (PLAP) from the cell surface.

As already discussed, PLAP is concentrated in lipid rafts, the more ordered bilayer microdomains that are enriched in sphingolipids and cholesterol (see Figure 5-10). Although PLAP and other GPI-anchored proteins lie in the opposite membrane leaflet from acyl-anchored proteins, both types of membrane proteins are concentrated in lipid rafts. In contrast, prenylated proteins are not found in lipid rafts.

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