| Description |
Mutations in Ras proteins have the potential to produce a constitutively active form of the protein that leads to oncogenesis. Ras proteins receive several posttranslational modifications which anchor them to the plasma membrane where they must be located to participate in signaling. Of the possible modifications, three are explored in this work: prenylation of the cysteine residue in a C-terminal CaaX recognition motif with either a farnesyl or geranylgeranyl group, removal of the three C-terminal (aaX) amino acids, where "a" is a small aliphatic amino acid and "X" determines whether a farnesyl or a geranylgeranyl group is added, and conversion of the carboxylate of the C-terminal prenylated cysteine to a methyl ester. Investigation of these modifications is undertaken to increase our understanding of the effects of the modifications, with the hope of identifying potential drug targets to terminate signaling in constitutively active proteins. Adsorption rates to supported lipid bilayers were measured for 5 peptides in various states of modification, including the unmodified peptide, a farnesylated peptide, a geranylgeranylated peptide, a farnesylated peptide missing the three C-terminal amino acids, and a peptide with all of the previous modifications and a C-terminal methyl ester. The adsorption rates indicate that the removal of the aaX amino acids had no effect on the adsorption of the peptides, while conversion of the C-terminal carboxylate to a methyl ester profoundly increased its adsorption to the bilayer. The results also suggest that the differential modification with either farnesyl or geranylgeranyl groups has the potential to target the peptide to certain subdomains within the plasma membrane. |
