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The Structural Basis of Oncogenic Mutations G12, G13 and Q61 in Small GTPase K-Ras4B

Shaoyong Lu1,2, Hyunbum Jang2, Ruth Nussinov2,3

  • 1Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, China.

Scientific Reports
|February 24, 2016
PubMed

Insights

Oncogenic mutations in K-Ras4B alter its conformation, affecting cancer development. Understanding these K-Ras4B mutations provides mechanistic insights into cancer-driving events.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Computational Biology

Background:

  • Ras proteins, including K-Ras4B, are crucial regulators of cell proliferation, survival, and differentiation.
  • Mutations at K-Ras4B residues G12, G13, and Q61 are common in human cancers and impair GTP hydrolysis, but their varying frequencies suggest distinct oncogenic mechanisms.

Purpose of the Study:

  • To elucidate the mechanisms underlying the differential oncogenicity of K-Ras4B mutations at G12, G13, and Q61.
  • To explain the varying mutation frequencies observed in K-Ras4B-driven cancers.

Main Methods:

  • Performed extensive molecular dynamics simulations (6.4 micros) on wild-type and mutant K-Ras4B (GTP/GDP-bound states).
  • Simulated complexes of wild-type and mutant K-Ras4B with GTPase-activating protein (GAP).
  • Investigated 'exchanged' nucleotide states to analyze conformational transitions during nucleotide exchange.

Main Results:

  • Wild-type K-Ras4B-GTP exists in both active and inactive conformations in solution.
  • Oncogenic mutations induce an inactive-to-active conformational transition in K-Ras4B-GTP.
  • Mutations K-Ras4B(G12C/G12D)-GDP expose the bound nucleotide, facilitating GDP-to-GTP exchange.
  • Conformational transitions are more accessible during GTP-to-GDP hydrolysis than GDP-to-GTP exchange.
  • GAP stabilizes the active conformation and organizes catalytic residue Q61; mutations disrupt this organization, impairing GTP hydrolysis.

Conclusions:

  • The study provides a mechanistic explanation for the differential oncogenicity of K-Ras4B mutations.
  • Findings illuminate the varying mutation frequencies in K-Ras4B-driven cancers.
  • The results offer a deeper understanding of key oncogenic events involving K-Ras4B.

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