{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Chen TJ"],"funding":["Ministry of Science and Technology, Taiwan"],"pagination":["105"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6420622"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["2"],"pubmed_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."],"journal":["Communications biology"],"pubmed_title":["Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation."],"pmcid":["PMC6420622"],"funding_grant_id":["MOST-105-2314-B-007 -001"],"pubmed_authors":["Wu YF","Wu JW","Hsu SC","Chen TJ","Liu YY","Wu MC","Lu CH","Kung HJ","Wang WC","Cheng HH","Liu JS","Wang HJ"],"additional_accession":[]},"is_claimable":false,"name":"Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation.","description":"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.","dates":{"release":"2019-01-01T00:00:00Z","publication":"2019","modification":"2026-05-03T19:01:36.137Z","creation":"2019-06-06T21:00:15Z"},"accession":"S-EPMC6420622","cross_references":{"pubmed":["30911680"],"doi":["10.1038/s42003-019-0343-4"]}}