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Related Experiment Videos

Structural differences between a ras oncogene protein and the normal protein.

L A Tong1, A M de Vos, M V Milburn

  • 1Department of Chemistry, University of California, Berkeley 94720.

Nature
|January 5, 1989
PubMed
Summary
This summary is machine-generated.

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A common cancer-causing mutation in the normal c-Ha-ras gene, replacing glycine with valine at position 12, alters the ras protein structure. This structural change in the p21(Val-12) protein impairs GTPase activity, leading to prolonged cell signaling and transformation.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Oncology

Background:

  • The c-Ha-ras gene is frequently mutated in human tumors, with a common alteration involving glycine to valine substitution at position 12.
  • This specific mutation in the ras oncogene is linked to cellular transformation and cancer development.

Purpose of the Study:

  • To elucidate the structural basis for cellular transformation caused by the glycine-to-valine substitution at position 12 in the c-Ha-ras gene.
  • To understand how this single amino acid change impacts the normal function of the ras protein.

Main Methods:

  • Determined the crystal structure of the GDP-bound form of the mutant ras protein, p21(Val-12), at 2.2 Angstrom resolution.
  • Compared the structure of the mutant p21(Val-12) protein with the wild-type c-Ha-ras protein.

Related Experiment Videos

Main Results:

  • The crystal structure of p21(Val-12) reveals significant structural differences compared to the normal c-Ha-ras protein.
  • A key difference is an enlarged loop in the mutant protein responsible for binding the beta-phosphate of guanine nucleotides.
  • This altered conformation at the 'catalytic site' is associated with reduced GTPase activity.

Conclusions:

  • The structural modification in p21(Val-12) due to the Val-12 substitution leads to impaired GTPase activity.
  • This reduced activity results in the mutant ras protein remaining in the GTP-bound, 'signal on' state for extended periods.
  • Prolonged signaling by the mutant ras protein is the underlying cause of cell transformation and cancer development.