Posttranslational Modification Of Ras And Other G Proteins

Small G proteins are synthesized in the cytosol of cells as an inactive precursor. Most of them require several post-translational modifications by proteolysis and addition of lipids at the "CAAX" tetrapeptide in their carboxyl termini that are crucial for their action (7). In the tetrapeptide "CAAX," "C" represents a cysteine residue, "A" represents an aliphatic amino acid (usually valine, leucine, or

FIGURE 1 A simplified schema of post-translational modification of Ras. Abbreviations: AAX, a tripeptide of an aliphatic amino acid-an aliphatic amino acid-a different amino acid; FDP, farnesyl diphosphate; FTase, farnesyl trasferase; GGDP, geranylgeranyl diphosphate; GGTase I, type I geranylgeranyltransferase; Ile, isoleucine; Leu, leucine; Met, methionine; Pal CoA, palmitoyl coenzyme A; SAM, S-adenosyl-L-methionine; Ser, serine.

FIGURE 1 A simplified schema of post-translational modification of Ras. Abbreviations: AAX, a tripeptide of an aliphatic amino acid-an aliphatic amino acid-a different amino acid; FDP, farnesyl diphosphate; FTase, farnesyl trasferase; GGDP, geranylgeranyl diphosphate; GGTase I, type I geranylgeranyltransferase; Ile, isoleucine; Leu, leucine; Met, methionine; Pal CoA, palmitoyl coenzyme A; SAM, S-adenosyl-L-methionine; Ser, serine.

isoleucine), and "X" may represent different amino acids that influence the way in which the protein is modified. The first and most important post-translational modification is prenylation, which is the covalent addition of either a farnesyl (15-carbon) or a geranylgeranyl (20-carbon) isoprenoid group to the cysteine residue at the "CAAX" tetrapeptide (Fig. 1). Three classes of isoprenyltransferase enzymes have been identified in mammalian cells, including protein farnesyl transferase (FTase), type I protein geranylgeranyltransferase (GGTase-I), and type II protein geranylgeranyltransferase (GGTase-II). FTase is a heterodimeric zinc metalloenzyme composed of a 48-kilodalton alpha-subunit and 46-kilodalton beta-subunit. FTase catalyzes farnesylation of proteins in which X is methionine, serine, alanine, glutamine, or cysteine (e.g., Ras, Lamin B, Rho B) and GGTase-I catalyzes geranylgeranylation of proteins in which X is leucine, isoleucine, or phenyl-alanine (e.g., Rho, Rap, and Rac). GGTase-II catalyzes the geranylgeranylation of sequences CXC, CCX, or XXCC (e.g., Rab proteins). Both FTase and/or GGTase have been considered as potential therapeutic targets (8-12). FTase have many substrates in the mammalian cells, indicating that inhibition of this pathway is not specific in cancer cells and may result in unwanted toxicities.

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