Structural Investigation of a Dimeric Variant of Pyruvate Kinase Muscle Isoform 2

Srivastava, Dhiraj; Razzaghi, Mortezaali; Henzl, Michael T.; Dey, Mishtu

doi:10.1021/acs.biochem.7b01013

Structural Investigation of a Dimeric Variant of Pyruvate Kinase Muscle Isoform 2

Journal Article · Mon Nov 27 23:00:00 EST 2017 · Biochemistry

DOI:https://doi.org/10.1021/acs.biochem.7b01013· OSTI ID:1423366

Srivastava, Dhiraj ^[1]; Razzaghi, Mortezaali ^[1]; Henzl, Michael T. ^[2]; ^[1]

Univ. of Iowa, Iowa City, IA (United States)
Univ. of Missouri—Columbia, MO (United States)

Pyruvate kinase muscle isoform 2 (PKM2) catalyzes the terminal step in glycolysis, transferring a phosphoryl group from phosphoenolpyruvate to ADP, to produce pyruvate and ATP. PKM2 activity is allosterically regulated by fructose 1,6-bisphosphate (FBP), an upstream glycolytic intermediate. FBP stabilizes the tetrameric form of the enzyme. In its absence, the PKM2 tetramers dissociate, yielding a dimer–monomer mixture having lower enzymatic activity. Here, the S437Y variant of PKM2 is incapable of binding FBP. Consistent with that defect, we find that S437Y exists in a monomer–dimer equilibrium in solution, with a K_d of ~20 μM. Interestingly, however, the protein crystallizes as a tetramer, providing insight into the structural basis for impaired FBP binding of S437Y.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Science Foundation

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1423366

Journal Information:: Biochemistry, Journal Name: Biochemistry Journal Issue: 50 Vol. 56; ISSN 0006-2960

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (26)

Using Situs for the integration of multi-resolution structures Wriggers, Willy Biophysical Reviews, Vol. 2, Issue 1 https://doi.org/10.1007/s12551-009-0026-3	journal	January 2010
Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with Oct-4 in regulating transcription Lee, Jungwoon; Kim, Hye Kyoung; Han, Yong-Mahn The International Journal of Biochemistry & Cell Biology, Vol. 40, Issue 5 https://doi.org/10.1016/j.biocel.2007.11.009	journal	January 2008
Accurate SAXS Profile Computation and its Assessment by Contrast Variation Experiments Schneidman-Duhovny, Dina; Hammel, Michal; Tainer, John A. Biophysical Journal, Vol. 105, Issue 4 https://doi.org/10.1016/j.bpj.2013.07.020	journal	August 2013
Pyruvate Kinase M2 Is a PHD3-Stimulated Coactivator for Hypoxia-Inducible Factor 1 Luo, Weibo; Hu, Hongxia; Chang, Ryan Cell, Vol. 145, Issue 5 https://doi.org/10.1016/j.cell.2011.03.054	journal	May 2011
Mitogenic and Oncogenic Stimulation of K433 Acetylation Promotes PKM2 Protein Kinase Activity and Nuclear Localization Lv, Lei; Xu, Yan-Ping; Zhao, Di Molecular Cell, Vol. 52, Issue 3 https://doi.org/10.1016/j.molcel.2013.09.004	journal	November 2013
Succinyl-5-aminoimidazole-4-carboxamide-1-ribose 5′-Phosphate (SAICAR) Activates Pyruvate Kinase Isoform M2 (PKM2) in Its Dimeric Form Yan, Ming; Chakravarthy, Srinivas; Tokuda, Joshua M. Biochemistry, Vol. 55, Issue 33 https://doi.org/10.1021/acs.biochem.6b00658	journal	August 2016
Structural Basis for Tumor Pyruvate Kinase M2 Allosteric Regulation and Catalysis ^† ^, ^‡ Dombrauckas, Jill D.; Santarsiero, Bernard D.; Mesecar, Andrew D. Biochemistry, Vol. 44, Issue 27 https://doi.org/10.1021/bi0474923	journal	July 2005
Differentiating a Ligand's Chemical Requirements for Allosteric Interactions from Those for Protein Binding. Phenylalanine Inhibition of Pyruvate Kinase ^† ^, ^‡ Williams, Rachel; Holyoak, Todd; McDonald, Gissel Biochemistry, Vol. 45, Issue 17 https://doi.org/10.1021/bi0524262	journal	May 2006
Distinguishing the Interactions in the Fructose 1,6-Bisphosphate Binding Site of Human Liver Pyruvate Kinase That Contribute to Allostery Ishwar, Arjun; Tang, Qingling; Fenton, Aron W. Biochemistry, Vol. 54, Issue 7 https://doi.org/10.1021/bi501426w	journal	February 2015
Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation Yang, Weiwei; Xia, Yan; Ji, Haitao Nature, Vol. 480, Issue 7375 https://doi.org/10.1038/nature10598	journal	December 2011
Serine is a natural ligand and allosteric activator of pyruvate kinase M2 Chaneton, Barbara; Hillmann, Petra; Zheng, Liang Nature, Vol. 491, Issue 7424 https://doi.org/10.1038/nature11540	journal	October 2012
ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect Yang, Weiwei; Zheng, Yanhua; Xia, Yan Nature Cell Biology, Vol. 14, Issue 12 https://doi.org/10.1038/ncb2629	journal	November 2012
PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis Yang, Liangchun; Xie, Min; Yang, Minghua Nature Communications, Vol. 5, Issue 1 https://doi.org/10.1038/ncomms5436	journal	July 2014
A survey of proteins encoded by non-synonymous single nucleotide polymorphisms reveals a significant fraction with altered stability and activity Allali-Hassani, Abdellah; Wasney, Gregory A.; Chau, Irene Biochemical Journal, Vol. 424, Issue 1 https://doi.org/10.1042/BJ20090723	journal	October 2009
Activation of Liver Pyruvate Kinase by Fructose 1,6-Diphosphate Taylor, C. B.; Bailey, E. Biochemical Journal, Vol. 102, Issue 2 https://doi.org/10.1042/bj1020032C	journal	February 1967
M2 pyruvate kinase provides a mechanism for nutrient sensing and regulation of cell proliferation Morgan, H. P.; O'Reilly, F. J.; Wear, M. A. Proceedings of the National Academy of Sciences, Vol. 110, Issue 15 https://doi.org/10.1073/pnas.1217157110	journal	March 2013
l-cysteine reversibly inhibits glucose-induced biphasic insulin secretion and ATP production by inactivating PKM2 Nakatsu, Daiki; Horiuchi, Yuta; Kano, Fumi Proceedings of the National Academy of Sciences, Vol. 112, Issue 10 https://doi.org/10.1073/pnas.1417197112	journal	February 2015
FoXS, FoXSDock and MultiFoXS: Single-state and multi-state structural modeling of proteins and their complexes based on SAXS profiles Schneidman-Duhovny, Dina; Hammel, Michal; Tainer, John A. Nucleic Acids Research, Vol. 44, Issue W1 https://doi.org/10.1093/nar/gkw389	journal	May 2016
New developments in the ATSAS program package for small-angle scattering data analysis Petoukhov, Maxim V.; Franke, Daniel; Shkumatov, Alexander V. Journal of Applied Crystallography, Vol. 45, Issue 2 https://doi.org/10.1107/S0021889812007662	journal	March 2012
Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses Anastasiou, D.; Poulogiannis, G.; Asara, J. M. Science, Vol. 334, Issue 6060 https://doi.org/10.1126/science.1211485	journal	November 2011
SAICAR Stimulates Pyruvate Kinase Isoform M2 and Promotes Cancer Cell Survival in Glucose-Limited Conditions Keller, K. E.; Tan, I. S.; Lee, Y. -S. Science, Vol. 338, Issue 6110 https://doi.org/10.1126/science.1224409	journal	October 2012
PKM2, a Central Point of Regulation in Cancer Metabolism Wong, Nicholas; De Melo, Jason; Tang, Damu International Journal of Cell Biology, Vol. 2013 https://doi.org/10.1155/2013/242513	journal	January 2013
Current Status of Tumor M2 Pyruvate Kinase (Tumor M2-PK) as a Biomarker of Gastrointestinal Malignancy Hathurusinghe, Harsha R.; Goonetilleke, Kolitha S.; Siriwardena, Ajith K. Annals of Surgical Oncology, Vol. 14, Issue 10 https://doi.org/10.1245/s10434-007-9481-x	journal	June 2007
In Silico Screening, Genotyping, Molecular Dynamics Simulation and Activity Studies of SNPs in Pyruvate Kinase M2 Kalaiarasan, Ponnusamy; Kumar, Bhupender; Chopra, Rupali PLOS ONE, Vol. 10, Issue 3 https://doi.org/10.1371/journal.pone.0120469	journal	March 2015
PKM2 and cancer: The function of PKM2 beyond glycolysis Dong, Gaochao; Mao, Qixing; Xia, Wenjie Oncology Letters, Vol. 11, Issue 3 https://doi.org/10.3892/ol.2016.4168	journal	January 2016
Cancer metabolism meets systems biology: Pyruvate kinase isoform PKM2 is a metabolic master regulator Filipp, FabianV Journal of Carcinogenesis, Vol. 12, Issue 1 https://doi.org/10.4103/1477-3163.115423	journal	January 2013

Cited By (1)

Purification and Characterization of Prolyl Hydroxylase 3/Pyruvate Kinase Isoform 2 Protein Complex Kumar, Sunil; Patel, Ashok Kumar Molecular Biotechnology, Vol. 62, Issue 2 https://doi.org/10.1007/s12033-019-00228-9	journal	November 2019

Similar Records

Structural basis for allosteric regulation of pyruvate kinase M2 by phosphorylation and acetylation

Journal Article · Mon Nov 30 23:00:00 EST 2020 · Journal of Biological Chemistry · OSTI ID:1765218

The 2.4 Å structure of Zymomonas mobilis pyruvate kinase: Implications for stability and regulation

Journal Article · Fri Jun 30 00:00:00 EDT 2023 · Archives of Biochemistry and Biophysics · OSTI ID:2423941

Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Journal Article · Sun Aug 26 00:00:00 EDT 2012 · Nature Chemical Biology · OSTI ID:1054015

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
analytical ultracentrifuge
chemical structure
crystal structure
glycolysis
monomers
oligomers
peptides and proteins
pyruvate kinase
size-exclusion chromatography
small angle X-ray scattering

Structural Investigation of a Dimeric Variant of Pyruvate Kinase Muscle Isoform 2

Citation Formats

References (26)

Cited By (1)

Similar Records

Related Subjects