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

  • Author(s): Chen, Tsan-Jan
  • Wang, Hung-Jung
  • Liu, Jai-Shin
  • Cheng, Hsin-Hung
  • Hsu, Sheng-Chieh
  • Wu, Meng-Chen
  • Lu, Chien-Hung
  • Wu, Yu-Fang
  • Wu, Jing-Wen
  • Liu, Ying-Yuan
  • Kung, Hsing-Jien
  • Wang, Wen-Ching
  • et al.
Abstract

PKM2 is a key metabolic enzyme central to glucose metabolism and energy expenditure. Multiple stimuli regulate PKM2's activity through allosteric modulation and post-translational modifications. Furthermore, PKM2 can partner with KDM8, an oncogenic demethylase and enter the nucleus to serve as a HIF1α co-activator. Yet, the mechanistic basis of the exon-10 region in allosteric regulation and nuclear translocation remains unclear. Here, we determined the crystal structures and kinetic coupling constants of exon-10 tumor-related mutants (H391Y and R399E), showing altered structural plasticity and reduced allostery. Immunoprecipitation analysis revealed increased interaction with KDM8 for H391Y, R399E, and G415R. We also found a higher degree of HIF1α-mediated transactivation activity, particularly in the presence of KDM8. Furthermore, overexpression of PKM2 mutants significantly elevated cell growth and migration. Together, PKM2 exon-10 mutations lead to structure-allostery alterations and increased nuclear functions mediated by KDM8 in breast cancer cells. Targeting the PKM2-KDM8 complex may provide a potential therapeutic intervention.

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