Malaria protein kinase CK2 (PfCK2) shows novel mechanisms of regulation

Michele Graciotti, Mahmood Alam, Lev Solyakov, Ralf Schmid, Glenn Burley, Andrew R Bottrill, Christian Doerig, Paul Cullis, Andrew B Tobin

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Casein kinase 2 (protein kinase CK2) is a conserved eukaryotic serine/theronine kinase with multiple substrates and roles in the regulation of cellular processes such as cellular stress, cell proliferation and apoptosis. Here we report a detailed analysis of the Plasmodium falciparum CK2, PfCK2, demonstrating that this kinase, like the mammalian orthologue, is a dual specificity kinase able to phosphorylate at both serine and tyrosine. However, unlike the human orthologue that is auto-phosphorylated on tyrosine within the activation loop, PfCK2 shows no activation loop auto-phosphorylation but rather is auto-phosphorylated at threonine 63 within subdomain I. Phosphorylation at this site in PfCK2 is shown here to regulate the intrinsic kinase activity of PfCK2. Furthermore, we generate an homology model of PfCK2 in complex with the known selective protein kinase CK2 inhibitor, quinalizarin, and in so doing identify key co-ordinating residues in the ATP binding pocket that could aid in designing selective inhibitors to PfCK2.
LanguageEnglish
Article numbere85391
Number of pages8
JournalPLoS One
Volume9
Issue number3
DOIs
Publication statusPublished - 21 Mar 2014

Fingerprint

Casein Kinase II
protein kinases
malaria
Malaria
phosphotransferases (kinases)
Phosphorylation
Phosphotransferases
automobiles
serine
Tyrosine
tyrosine
dual-specificity kinase
Chemical activation
Protein-Serine-Threonine Kinases
protein phosphorylation
Cell proliferation
Plasmodium falciparum
Threonine
Protein Kinase Inhibitors
threonine

Keywords

  • crystal structure
  • kinase inhibitor
  • in vitro kinase assay

Cite this

Graciotti, M., Alam, M., Solyakov, L., Schmid, R., Burley, G., Bottrill, A. R., ... Tobin, A. B. (2014). Malaria protein kinase CK2 (PfCK2) shows novel mechanisms of regulation. PLoS One, 9(3), [e85391]. https://doi.org/10.1371/journal.pone.0085391
Graciotti, Michele ; Alam, Mahmood ; Solyakov, Lev ; Schmid, Ralf ; Burley, Glenn ; Bottrill, Andrew R ; Doerig, Christian ; Cullis, Paul ; Tobin, Andrew B. / Malaria protein kinase CK2 (PfCK2) shows novel mechanisms of regulation. In: PLoS One. 2014 ; Vol. 9, No. 3.
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Graciotti, M, Alam, M, Solyakov, L, Schmid, R, Burley, G, Bottrill, AR, Doerig, C, Cullis, P & Tobin, AB 2014, 'Malaria protein kinase CK2 (PfCK2) shows novel mechanisms of regulation' PLoS One, vol. 9, no. 3, e85391. https://doi.org/10.1371/journal.pone.0085391

Malaria protein kinase CK2 (PfCK2) shows novel mechanisms of regulation. / Graciotti, Michele; Alam, Mahmood ; Solyakov, Lev; Schmid, Ralf; Burley, Glenn; Bottrill, Andrew R; Doerig, Christian; Cullis, Paul; Tobin, Andrew B.

In: PLoS One, Vol. 9, No. 3, e85391, 21.03.2014.

Research output: Contribution to journalArticle

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AB - Casein kinase 2 (protein kinase CK2) is a conserved eukaryotic serine/theronine kinase with multiple substrates and roles in the regulation of cellular processes such as cellular stress, cell proliferation and apoptosis. Here we report a detailed analysis of the Plasmodium falciparum CK2, PfCK2, demonstrating that this kinase, like the mammalian orthologue, is a dual specificity kinase able to phosphorylate at both serine and tyrosine. However, unlike the human orthologue that is auto-phosphorylated on tyrosine within the activation loop, PfCK2 shows no activation loop auto-phosphorylation but rather is auto-phosphorylated at threonine 63 within subdomain I. Phosphorylation at this site in PfCK2 is shown here to regulate the intrinsic kinase activity of PfCK2. Furthermore, we generate an homology model of PfCK2 in complex with the known selective protein kinase CK2 inhibitor, quinalizarin, and in so doing identify key co-ordinating residues in the ATP binding pocket that could aid in designing selective inhibitors to PfCK2.

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Graciotti M, Alam M, Solyakov L, Schmid R, Burley G, Bottrill AR et al. Malaria protein kinase CK2 (PfCK2) shows novel mechanisms of regulation. PLoS One. 2014 Mar 21;9(3). e85391. https://doi.org/10.1371/journal.pone.0085391