5x0i

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Crystal structure of PKM2 R399E mutant complexed with FBP and serine

Structural highlights

5x0i is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.64Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KPYM_HUMAN Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. Stimulates POU5F1-mediated transcriptional activation. Plays a general role in caspase independent cell death of tumor cells. The ratio betwween the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival.^[1] ^[2] ^[3]

Publication Abstract from PubMed

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 HIF1alpha 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 HIF1alpha-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.

Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation.,Chen TJ, Wang HJ, Liu JS, Cheng HH, Hsu SC, Wu MC, Lu CH, Wu YF, Wu JW, Liu YY, Kung HJ, Wang WC Commun Biol. 2019 Mar 15;2:105. doi: 10.1038/s42003-019-0343-4. eCollection 2019. PMID:30911680^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Stetak A, Veress R, Ovadi J, Csermely P, Keri G, Ullrich A. Nuclear translocation of the tumor marker pyruvate kinase M2 induces programmed cell death. Cancer Res. 2007 Feb 15;67(4):1602-8. PMID:17308100 doi:10.1158/0008-5472.CAN-06-2870
↑ Lee J, Kim HK, Han YM, Kim J. Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with Oct-4 in regulating transcription. Int J Biochem Cell Biol. 2008;40(5):1043-54. doi: 10.1016/j.biocel.2007.11.009., Epub 2007 Nov 29. PMID:18191611 doi:10.1016/j.biocel.2007.11.009
↑ Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A, Semenza GL. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011 May 27;145(5):732-44. doi: 10.1016/j.cell.2011.03.054. PMID:21620138 doi:10.1016/j.cell.2011.03.054
↑ Chen TJ, Wang HJ, Liu JS, Cheng HH, Hsu SC, Wu MC, Lu CH, Wu YF, Wu JW, Liu YY, Kung HJ, Wang WC. Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation. Commun Biol. 2019 Mar 15;2:105. doi: 10.1038/s42003-019-0343-4. eCollection 2019. PMID:30911680 doi:http://dx.doi.org/10.1038/s42003-019-0343-4