Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation.
Commun Biol
; 2: 105, 2019.
Article
em En
| MEDLINE
| ID: mdl-30911680
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Hormônios Tireóideos
/
Proteínas de Transporte
/
Éxons
/
Proteínas de Membrana
/
Mutação
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Commun Biol
Ano de publicação:
2019
Tipo de documento:
Article