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


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Article Info

DATE

2019-12

AUTHORS

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

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. More... »

PAGES

105

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s42003-019-0343-4

DOI

http://dx.doi.org/10.1038/s42003-019-0343-4

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112759339

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30911680


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Download the RDF metadata as:  json-ld nt turtle xml License info

HOW TO GET THIS DATA PROGRAMMATICALLY:

JSON-LD is a popular format for linked data which is fully compatible with JSON.

curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1038/s42003-019-0343-4'

N-Triples is a line-based linked data format ideal for batch operations.

curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1038/s42003-019-0343-4'

Turtle is a human-readable linked data format.

curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1038/s42003-019-0343-4'

RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/s42003-019-0343-4'


 

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