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Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation

Tsan-Jan Chen1, Hung-Jung Wang2, Jai-Shin Liu1

  • 11Institute of Molecular and Cellular Biology and Department of Life Science, National Tsing-Hua University, Hsinchu, 30013 Taiwan.

Communications Biology
|March 27, 2019
PubMed

Insights

Mutations in pyruvate kinase M2 (PKM2) exon 10 alter its structure and allosteric regulation. This promotes interaction with KDM8, enhancing cancer cell growth and migration, suggesting a therapeutic target.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Biology

Background:

  • Pyruvate kinase M2 (PKM2) is a crucial enzyme in glucose metabolism, regulated by various stimuli.
  • PKM2 interacts with KDM8, a demethylase, to function as a HIF1α co-activator in the nucleus.
  • The role of the PKM2 exon-10 region in allosteric regulation and nuclear translocation is not well understood.

Purpose of the Study:

  • To investigate the mechanistic role of the PKM2 exon-10 region in allosteric regulation and nuclear translocation.
  • To analyze the impact of tumor-related mutations in PKM2 exon 10 on its structure, function, and interaction with KDM8.
  • To evaluate the effect of PKM2 mutations on HIF1α activity, cell growth, and migration in breast cancer cells.

Main Methods:

  • Determined crystal structures and kinetic coupling constants of PKM2 exon-10 mutants (H391Y, R399E).
  • Utilized immunoprecipitation assays to assess the interaction between PKM2 mutants and KDM8.
  • Measured HIF1α-mediated transactivation activity and evaluated cell growth and migration upon overexpression of PKM2 mutants.

Main Results:

  • PKM2 exon-10 mutants (H391Y, R399E) exhibited altered structural plasticity and reduced allosteric regulation.
  • Mutations H391Y, R399E, and G415R showed increased interaction with KDM8.
  • PKM2 mutants enhanced HIF1α transactivation, particularly with KDM8, and significantly increased cell growth and migration.

Conclusions:

  • Mutations in the PKM2 exon-10 region disrupt structure-allostery coupling and enhance nuclear functions via KDM8 in breast cancer.
  • The PKM2-KDM8 complex emerges as a potential therapeutic target for breast cancer treatment.

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