In eukaryotic cells, covalently attached lipids anchor some otherwise typically water-soluble proteins to one or the other leaflet of the membrane. In such lipid-anchored proteins, the hydrocarbon chains of the lipid anchor are embedded in the bilayer, but the protein itself does not enter the bilayer. The lipid anchors used to anchor proteins to the cytosolic face are not used for the exoplasmic face, and vice versa.

One group of cytosolic proteins is anchored to the cytosolic face of a membrane by a fatty acyl group (e.g., myristate or palmitate) covalently attached to an N-terminal glycine residue, a modification called acylation (Figure 7-19a). 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, induces abnormal cellular growth that can lead to cancer, but does so only when it has a myristylated N-terminus.

A second group of cytosolic proteins are anchored to membranes by a hydrocarbon chain attached to a cysteine residue at or near the C-terminus, a modification called prenylation (Figure 7-19b). Prenyl anchors are built from 5-carbon isoprene units, which, as detailed in the following section, are also used in the synthesis of cholesterol. In prenylation, a 15-carbon farnesyl or 20-carbon geranylgeranyl group is bound by a thioether bond to the –SH group of a C-terminal cysteine residue of the protein, usually part of a C-terminal Cys-Ala-Ala-X (X = any of a number of amino acids) or CAAX box. Once prenylation has occurred, the C-terminal Ala-Ala-X motif may be removed by proteolysis. In some cases, a second geranylgeranyl group or a fatty acyl palmitate group is linked to a nearby cysteine residue. The additional hydrocarbon anchor is thought to reinforce the attachment of the protein to the membrane. For example, Ras, a GTPase superfamily protein that functions in intracellular signaling (see Chapter 15), is recruited to the cytosolic face of the plasma membrane by such a double anchor. Rab proteins, which also belong to the GTPase superfamily, are similarly bound to the cytosolic surface of intracellular vesicles by prenyl anchors; these proteins are required for the fusion of vesicles with their target membranes (see Chapter 14). Yet other proteins are palmitoylated on membrane-proximal cysteine residues in the absence of other lipid modifications.

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Some cell-surface proteins, and some specialized proteins with distinctive covalently attached polysaccharides called proteoglycans (see Chapter 20), are bound to the exoplasmic face of the plasma membrane by a third anchor group, glycosylphosphatidylinositol (GPI) anchors. The exact structures of GPI anchors vary greatly among different cell types, but they always contain phosphatidylinositol, whose two fatty acyl chains extend into the lipid bilayer just like those of typical membrane phospholipids; phosphoethanolamine, which covalently links the anchor to the C-terminus of a protein; and several sugar residues (Figure 7-19c). Therefore, GPI anchors are glycolipids. The GPI anchor is both necessary and sufficient for binding proteins to the membrane. For instance, treatment of cells with phospholipase C, which cleaves the phosphate-glycerol bond in phospholipids and in GPI anchors (see Figure 7-12), releases GPI-anchored proteins such as Thy-1 and placental alkaline phosphatase (PLAP) from the cell surface.