A single activity carboxyl methylates both farnesyl and geranylgeranyl cysteine residues.
Members of the Ras superfamily of small GTP-binding proteins, gamma-subunits of heterotrimeric G proteins and nuclear lamin B are subject to a series of post-translational modifications that produce prenylcysteine methylester groups at their carboxyl termini. The thioether-linked polyisoprenoid substituent can be either farnesyl (C15) or geranylgeranyl (C20). Small molecule prenylcysteine derivatives with either the C15 or C20 modification, such as N-acetyl-S-trans,trans-farnesyl-L-cysteine (AFC), S-trans,trans-farnesylthiopropionate (FTP), as well as the corresponding geranylgeranyl derivatives (AGGC and GGTP) are substrates for the carboxyl methyltransferase. Saccharomyces cerevisiae ste14 mutants that lack RAS and a-factor carboxyl methyltransferase activity are also unable to methylate farnesyl and geranylgeranylcysteine derivatives. Moreover, C20-substituted cysteine analogs directly compete for carboxyl methylation with the C15-substituted cysteine analogs and vice versa. Finally, AGGC is even more effective than AFC as an inhibitor of Ras carboxyl methylation, despite the fact that Ras is methylated at a farnesylcysteine rather than a geranylgeranylcysteine residue.
Volker
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Department of Chemistry, Princeton University, New Jersey 08544.
Lane
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Kwee
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Johnson
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Stock
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D000818:Animals; D001921:Brain / Q000201:enzymology*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism; D004224:Diterpenes / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008745:Methylation; D011496:Protein Methyltransferases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013347:Subcellular Fractions / Q000201:enzymology; D013379:Substrate Specificity
D004224:Diterpenes; D011994:Recombinant Proteins; C065977:geranylgeranylcysteine; C057785:S-farnesylcysteine; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D003545:Cysteine