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Updated: Aug 7, 2025

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
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The Self-Association of the KRAS4b Protein is Altered by Lipid-Bilayer Composition and Electrostatics

Ki-Young Lee1, Mitsuhiko Ikura2, Christopher B Marshall2

  • 1Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Gyeonggi-Do, South Korea.

Angewandte Chemie (International Ed. in English)
|March 8, 2023
PubMed

Insights

KRAS protein self-assembly is crucial for cancer signaling. Anionic lipids like phosphatidylserine (PS) promote this, and we identified specific dimer structures and their environmental regulation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Signaling

Background:

  • KRAS is a key regulator of cellular signaling pathways.
  • Mutations in KRAS are implicated in approximately 30% of human cancers.
  • KRAS self-association is vital for activating downstream effectors like RAF and driving oncogenesis.

Purpose of the Study:

  • To elucidate the structural mechanisms by which anionic lipids, specifically phosphatidylserine (PS), promote KRAS self-association.
  • To investigate the impact of PS concentration on KRAS self-assembly dynamics.

Main Methods:

  • Utilized nanodisc bilayers with defined lipid compositions to mimic cell membranes.
  • Employed paramagnetic NMR experiments to probe KRAS self-association and dimer conformations.
  • Validated identified dimer interfaces using charge-reversal mutants.

Main Results:

  • Demonstrated the existence of two transient KRAS dimer conformations.
  • Identified alternate electrostatic contacts (R135 with D153 or E168) at the "α4/5-α4/5" interface.
  • Showed that lipid composition and salt concentration modulate the dynamic equilibrium of these dimer conformations.

Conclusions:

  • The plasticity of the KRAS dimerization interface is responsive to its membrane environment.
  • These findings provide structural insights into KRAS-membrane interactions and self-assembly.
  • The principles governing KRAS dimerization may extend to other membrane-associated signaling complexes.
Keywords:
KRAS DimersLipidsNMR SpectroscopyNanodiscsPlastic Interactions

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