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Allosteric Regulation of Switch-II Domain Controls KRAS Oncogenicity.

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Lysine 104 acetylation is critical for KRAS oncogenic activity. Targeting this site and its allosteric network offers a novel therapeutic strategy for KRAS-driven cancers.

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Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • RAS proteins, including KRAS, are key regulators of cellular processes.
  • KRAS activity relies on nucleotide binding, modulated by GEFs and GAPs.
  • Acetylation of KRAS at lysine 104 (K104) impacts its transforming capacity.

Purpose of the Study:

  • To investigate the in vivo effect of the K104Q mutation on KRAS oncogenic activity.
  • To elucidate the allosteric network involving K104 and its role in KRAS function.
  • To explore therapeutic strategies targeting the KRAS allosteric network.

Main Methods:

  • CRISPR-Cas9 gene editing to create mouse models with K104Q mutation.
  • Biochemical and structural analyses of KRAS mutations.
  • Assessment of oncogenic activity in vivo and in vitro.

Main Results:

  • The K104Q mutation alone did not cause loss of function but significantly attenuated KRASG12D oncogenic activity.
  • K104Q and G12D mutations cooperate to suppress GEF-mediated nucleotide exchange.
  • K104 is part of an allosteric network with switch-II residues (M72, R73, G75).
  • Mutation at G75 also demonstrated a negative regulatory effect on KRASG12D.

Conclusions:

  • Lysine 104 is essential for the full oncogenic potential of mutant KRAS.
  • The allosteric network involving K104 is crucial for KRAS oncogenicity.
  • Targeting this allosteric network presents a promising therapeutic avenue for KRAS-mutant cancers.