Comparison of the computed three-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 substitutions 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 Gln 61. To determine the effects of these substitutions on the three-dimensional structure of the whole p21 protein, we have performed molecular dynamics calculations on each of these three proteins bound to GDP and magnesium ion to compute the average structures of each of the three forms. Comparisons of the computed average structures shows that both oncogenic forms with Val 12 and Leu 61 differ substantially in structure from that of the wild type (containing Gly 12 and Gln 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, and several of them have already been found to be involved in the cellular 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 between transforming and nontransforming p21 mutant proteins neither of which binds nucleotide. The two oncogenic forms have similar conformations in their carboxyl-terminal domains, but differ in conformation at residues 32-47 and 55-74. The former region is known to be involved in the interaction with at least three downstream effector target proteins. Thus, differences in structure between the two oncogenic proteins may reflect different relative affinities of each oncogenic protein for each of these effector targets. The latter region, 55-74, is known to be a highly mobile segment of the protein. The results strongly suggest that critical oncogenic amino acid substitutions in the p21 protein cause changes in the structures of vital domains of this protein.
Monaco
R
R
Department of Chemistry, New York University, New York 10003, USA.
Chen
J M
JM
Chung
D
D
Brandt-Rauf
P
P
Pincus
M R
MR
D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D011905:Genes, ras; D006153:Guanosine Diphosphate / Q000378:metabolism*; D015513:Oncogene Proteins / Q000737:chemistry; D011487:Protein Conformation; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013816:Thermodynamics
D015513:Oncogene Proteins; D006153:Guanosine Diphosphate; D016283:Proto-Oncogene Proteins p21(ras)