Proteins
Proteins

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Proteins

2.4.2 Lipid-linked proteins and lipoproteins

Lipid-linked proteins are proteins that have been covalently modified by addition of one or more lipid groups. Note that the term lipoprotein, though sometimes used to describe lipid-linked proteins, is strictly applicable only to those proteins that associate with lipids non-covalently. These proteins have quite distinct functions. Lipoproteins serve to transport triacylglycerols and cholesterol in the blood plasma. We will not be discussing them any further at this point.

In lipid-linked proteins, the lipid component serves to anchor the protein in membranes. Some membrane-associated proteins are initially synthesised as soluble proteins in the cytosol before covalent addition of a lipid group.

  • Why does the addition of a lipid group cause proteins to locate to membranes?

  • The lipid groups are hydrophobic, so readily insert into membranes.

Proteins form covalent attachments to three different types of lipid, which are listed below. The structures of these lipid groups and the nature of their attachments to proteins are indicated in Figure 25.

Figure 25 Lipidation of proteins. Some proteins are modified by the covalent attachment of (a) isoprenoid groups, (b) fatty acyl groups or (c) glycoinositol phospholipids (GPIs).
  • Isoprenoid groups such as farnesyl and geranylgeranyl residues: the modified protein is described as ‘prenylated’.

  • Fatty acyl groups such as myristoyl and palmitoyl residues: the modified protein is described as ‘fatty acylated’.

  • Glycoinositol phospholipids (GPIs): the modified protein is described as ‘GPI-linked’.

Prenylation and fatty acylation localise proteins to the cytosolic surface of the plasma membrane or, in the case of myristoylated proteins, to membranes of the endoplasmic reticulum and the eukaryotic nucleus. In contrast, GPI linkages anchor proteins to the extracellular surface of the plasma membrane. Prenylation of proteins in the nucleus can target them to the inner surface of the nuclear membrane. Such is the case with lamins, components of the nuclear lamina.

The most common site of prenylation in proteins is via a thioether linkage (–S–) to a cysteine residue near the C-terminus of the polypeptide chain (Figure 25a). This critical Cys is the fourth from last residue at the C-terminus and is followed directly by two aliphatic (non-polar) residues. Thus the terminal sequence is given by CaaX, where ‘a’ denotes an aliphatic residue and ‘X’ is any amino acid residue.

The type of isoprenoid group that is linked to the protein depends on which amino acid X is. Thus, if X is Ala, Met or Ser, a farnesyl group is added at the Cys, whereas, if X is Leu, a geranylgeranyl group is added. With addition of the isoprenoid group, the aaX tripeptide is proteolytically removed and the terminal carboxyl group (belonging to the Cys) is esterified with a methyl group. The isoprenoid group, as well as anchoring the protein to a membrane, also seems to facilitate interaction of its attached protein with other membrane-associated proteins.

In fatty acylated eukaryotic proteins, the fatty acid groups that are covalently linked to the protein component are either myristic acid, a saturated C14 fatty acid, or palmitic acid, a saturated C16 fatty acid. An amide linkage connects myristic acid to the amino group of the protein's N-terminal glycine residue, whereas palmitic acid is connected to a specific Cys residue via a thioester bond (–CO–S–; Figure 25b). Myristoylation occurs during protein synthesis (translation) and this modification tends to remain for the lifetime of the protein. In contrast, palmitoylation occurs in the cytosol after the protein has been synthesised, and is reversible.

As well as serving to anchor the protein in membranes, palmitoylation affects protein–protein interactions and activity; the reversible nature of this modification permits regulation of a specific protein in, for example, intracellular signalling.

The complex chemical structure of the GPI anchor is illustrated in Figure 25c, in which the molecular components are identified. A phosphatidylinositol unit, which contains two fatty acyl chains, is linked via a glycosidic bond to one end of a tetrasaccharide and the other end of the tetrasaccharide is linked via a phosphoester bond to phosphoethanolamine. This whole structure is linked to the protein by means of an amide linkage between the amino group of phosphoethanolamine and the C-terminal carboxyl group of the protein. The fatty acyl groups and the sugars of the tetrasaccharide vary depending on which particular protein is modified in this way. The GPI anchor is added to newly synthesised proteins in the rough endoplasmic reticulum.

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