Structural effects of substitutions on the p21 proteins

Abstract

The conformational effects of different amino acid substitutions (lysine, serine, proline, and D-valine) for glycine at position 12 in the p21 oncogene-encoded proteins have been investigated by using conformational energy calculations. The normal cellular gene codes for a glycine at position 12 in the amino acid sequence, in the middle of a hydrophobic p21-(6-15)-decapepetide from Leu-6 to Gly-15. Mutations that cause amino acid substitutions for Gly-12 result in a protein product that produces malignant transformation of cells. We now find that not only are the preferred structures for the lysine- and serine-containing peptides more restricted and more helical than those for the glycine-containing peptide, but the lowest-energy structure for each substituted peptide is exactly the same as that previously found for the peptide with Val-12, suggesting the existence of a "malignancy-causing" conformation. None of the preferred conformations for the valine-, lysine-, and serine-containing peptides contain chain reversals at positions 11 and 12. However, we find that proline, unlike these residues but like glycine, at position 12 causes helix termination at positions 11 and 12, a result that suggests that the p21 protein product with proline at position 12 may exhibit lowered transforming potential, in agreement with the results of recent genetic recombination experiments.