COMPARISON OF THE COMPUTED 3-DIMENSIONAL STRUCTURES OF ONCOGENIC FORMS (BOUND TO GDP) OF THE RAS-GENE-ENCODED P21 PROTEIN WITH THE STRUCTURE OF THE NORMAL (NON-TRANSFORMING) WILD-TYPE PROTEIN

The ras-oncogene-encoded p21 protein becomes oncogenic if amino acid s ubstitutions occur at critical positions in the polypeptide chain. The most commonly found oncogenic forms contain Val in place of Gly 12 or Leu in place of Gin 61. To determine the effects of these substitutio ns on the three-dimensional structure of the whole p21 protein, we hav e performed molecular dynamics calculations on each of these three pro teins bound to GDP and magnesium ion to compute the average structures of each of the three forms. Comparisons of the computed average struc tures shows that both oncogenic forms with Val 12 and Leu 61 differ su bstantially in structure from that of the wild type (containing Gly 12 and Gin 61) in discrete regions: residues 10-16, 32-47, 55-74, 85-89, 100-110, and 119-134. All of these regions occur in exposed loops, an d several of them have already been found to be involved in the cellul ar functioning of the p21 protein. These regions have also previously been identified as the most flexible domains of the wild-type protein and have been bound to be the same ones that differ in conformation be tween transforming and nontransforming p21 mutant proteins neither of which binds nucleotide. The two oncogenic forms have similar conformat ions in their carboxyl-terminal domains, but differ in conformation at residues 32-47 and 55-74. The former region is known to be involved i n the interaction with at least three downstream effector target prote ins. Thus, differences in structure between the two oncogenic proteins may reflect different relative affinities of each oncogenic protein f or each of these effector targets. The latter region, 55-74, is known to be a highly mobile segment of the protein. The results strongly sug gest that critical oncogenic amino acid substitutions in the p21 prote in cause changes in the structures of vital domains of this protein.