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

Tsan Jan Chen, Hung Jung Wang, Jai Shin Liu, Hsin Hung Cheng, Sheng Chieh Hsu, Meng Chen Wu, Chien Hung Lu, Yu Fang Wu, Jing Wen Wu, Ying Yuan Liu, Hsing Jien Kung, Wen Ching Wang

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number105
JournalCommunications Biology
Volume2
Issue number1
DOIs
Publication statusPublished - Dec 1 2019
Externally publishedYes

Fingerprint

exons
Exons
mutation
Mutation
Allosteric Regulation
mutants
post-translational modification
Cell growth
transcriptional activation
Post Translational Protein Processing
Immunoprecipitation
cell movement
Metabolism
energy expenditure
breast neoplasms
Energy Metabolism
Transcriptional Activation
Cell Movement
Plasticity
Tumors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Medicine (miscellaneous)

Cite this

Chen, T. J., Wang, H. J., Liu, J. S., Cheng, H. H., Hsu, S. C., Wu, M. C., ... Wang, W. C. (2019). Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation. Communications Biology, 2(1), [105]. https://doi.org/10.1038/s42003-019-0343-4

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

In: Communications Biology, Vol. 2, No. 1, 105, 01.12.2019.

Research output: Contribution to journalArticle

Chen, TJ, Wang, HJ, Liu, JS, Cheng, HH, Hsu, SC, Wu, MC, Lu, CH, Wu, YF, Wu, JW, Liu, YY, Kung, HJ & Wang, WC 2019, 'Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation', Communications Biology, vol. 2, no. 1, 105. https://doi.org/10.1038/s42003-019-0343-4
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. / Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation. In: Communications Biology. 2019 ; Vol. 2, No. 1.
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