Journal of Protein Chemistry

, Volume 14, Issue 6, pp 457–466

Comparison of the computed three-dimensional structures of oncogenic forms (bound to GDP) of theras-Gene-Encoded p21 protein with the structure of the normal (non-transforming) wild-type protein

  • Regina Monaco
  • James M. Chen
  • Denise Chung
  • Paul Brandt-Rauf
  • Matthew R. Pincus
Article

DOI: 10.1007/BF01888140

Cite this article as:
Monaco, R., Chen, J.M., Chung, D. et al. J Protein Chem (1995) 14: 457. doi:10.1007/BF01888140

Abstract

Theras-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.

Key words

p21 protein oncogenic forms conformations molecular dynamics 

Copyright information

© Plenum Publishing Corporation 1995

Authors and Affiliations

  • Regina Monaco
    • 1
  • James M. Chen
    • 2
  • Denise Chung
    • 3
  • Paul Brandt-Rauf
    • 4
  • Matthew R. Pincus
    • 1
    • 5
    • 6
  1. 1.Department of ChemistryNew York UniversityNew York
  2. 2.Dupont Agricultural ProductsStein-Haskell Research CenterNewark
  3. 3.Department of ChemistryLong Island UniversityBrooklyn
  4. 4.Division of Environmental ScienceColumbia College of Physiciansm and SurgeonsNew York
  5. 5.Department of Pathology and Laboratory MedicineVeterans Affairs Medical CenterBrooklyn
  6. 6.Department of PathologySUNY Health Science CenterBrooklyn

Personalised recommendations