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GTP Binding and Oncogenic Mutations May Attenuate Hypervariable Region (HVR)-Catalytic Domain Interactions in Small

Shaoyong Lu1, Avik Banerjee2, Hyunbum Jang3

  • 1From the Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China, Cancer and Inflammation Program, Leidos Biomedical Research, Inc., NCI-Frederick, Frederick, Maryland 21702.

The Journal of Biological Chemistry
|October 11, 2015
PubMed

Insights

Oncogenic mutations in K-Ras4B can disrupt its normal function by weakening interactions between its hypervariable region (HVR) and catalytic domain. This disruption, seen in both GDP- and GTP-bound states, may lead to uncontrolled Ras signaling in cancer.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • K-Ras4B is a critical oncogene in cancer, regulating cell growth and survival.
  • Its C-terminal hypervariable region (HVR) is essential for biological activity and membrane interaction.
  • The HVR's interaction with the plasma membrane and catalytic domain differs between the active (GTP-bound) and inactive (GDP-bound) states.

Purpose of the Study:

  • To investigate the impact of nucleotides (GTP/GDP) and various oncogenic mutations on full-length K-Ras4B.
  • To elucidate how mutations affect the interaction between the HVR and the catalytic domain.
  • To understand the molecular mechanisms underlying K-Ras4B-driven oncogenesis.

Main Methods:

  • Molecular dynamics simulations.
  • Nuclear Magnetic Resonance (NMR) spectroscopy.
  • Analysis of full-length K-Ras4B with wild-type and mutant forms.

Main Results:

  • Wild-type GDP-bound K-Ras4B exhibits autoinhibition through tight HVR-catalytic domain interactions.
  • GTP-bound K-Ras4B shows looser HVR association, potentially releasing it for signaling.
  • Several oncogenic mutations weaken HVR-catalytic domain interactions in both nucleotide states, promoting HVR release.

Conclusions:

  • Oncogenic K-Ras4B mutations can promote signaling by weakening HVR-catalytic domain interactions, independent of nucleotide status.
  • Mutations may abolish GTP hydrolysis and facilitate effector binding, contributing to cancer progression.
  • K-Ras4B mutations can dysregulate signaling through multiple mechanisms, not solely by affecting GTP hydrolysis.
Keywords:
Ras proteinbiophysicscomputational biologynuclear magnetic resonance (NMR)protein conformationprotein dynamic

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