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

• Published in: Communications biology 2019-03, Vol.2 (1), p.105-105, Article 105
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 14/19; 631/45; 631/535; 692/699/67/1347; 82/83; Active Transport, Cell Nucleus; Allosteric properties; Allosteric Regulation; Biology; Biomedical and Life Sciences; Breast cancer; Carrier Proteins - chemistry; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell migration; Energy expenditure; Energy metabolism; Exons; Glucose metabolism; Histone Demethylases - chemistry; Histone Demethylases - genetics; Histone Demethylases - metabolism; Humans; Immunohistochemistry; Immunoprecipitation; Kinases; Life Sciences; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; Models, Molecular; Mutants; Mutation; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Nuclear transport; Post-translation; Protein Conformation; Pyruvate kinase; Pyruvic acid; Thyroid Hormone-Binding Proteins; Thyroid Hormones - chemistry; Thyroid Hormones - genetics; Thyroid Hormones - metabolism
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-019-0343-4

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. Tsan-Jan Chen, Hung-Jung Wang et al. report the crystal structures of tumor-related mutant forms of pyruvate kinase M2 (PKM2). They show that these mutations lead to increased interaction with the PKM2 binding partner KDM8, suggesting a mechanism for their oncogenic action.