<Emphasis Type="Italic">Plasmodium falciparum</Emphasis> possesses a unique dual-specificity serine/threonine and tyrosine kinase,Pfnek3 |
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Authors: | Huiyu?Low Chun?Song?Chua Email author" target="_blank">Tiow-Suan?SimEmail author |
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Institution: | (1) Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Block MD4A #04-02, 5 Science Drive 2, Singapore, 117597, Singapore; |
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Abstract: | Despite the absence of classical tyrosine kinases encrypted in the kinome of Plasmodium falciparum, biochemical analyses have detected significant tyrosine phosphorylation in its cell lysates. Supporting such phosphorylation
is critical for parasite development. These observations have thus raised queries regarding the plasmodial enzymes accountable
for tyrosine kinase activities in vivo. In the current investigation, immunoblot analysis intriguingly demonstrated that Pfnek3,
a plasmodial mitogen-activated protein kinase kinase (MAPKK), displayed both serine/threonine and tyrosine kinase activities
in autophosphorylation reactions as well as in phosphorylation of the exogenous myelin basic protein substrate. The results
obtained strongly support Pfnek3 as a novel dual-specificity kinase of the malarial parasite, even though it displays a HGDLKSTN
motif in the catalytic loop that resembles the consensus HRDLKxxN signature found in the serine/threonine kinases. Notably,
its serine/threonine and tyrosine kinase activities were found to be distinctly influenced by Mg2+ and Mn2+ cofactors. Further probing into the regulatory mechanism of Pfnek3 also revealed tyrosine phosphorylation to be a crucial
factor that stimulates its kinase activity. Through biocomputational analyses and functional assays, tyrosine residues Y117,
Y122, Y172, and Y238 were proposed as phosphorylation sites essential for mediating the catalytic activities of Pfnek3. The
discovery of Pfnek3’s dual role in phosphorylation marks its importance in closing the loop for cellular regulation in P. falciparum, which remains elusive to date. |
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