Eukaryotic initiation factor 2alpha kinase is a nitric oxide-responsive mercury sensor enzyme: potent inhibition of catalysis by the mercury cation and reversal by nitric oxide |
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| Authors: | Martinkova Marketa Igarashi Jotaro Shimizu Toru |
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| Affiliation: | Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Sendai 980-8577, Japan. |
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| Abstract: | The activity of one of the eukaryotic initiation factor 2alpha kinases, heme-regulated inhibitor (HRI), is modulated by heme binding. Here, we demonstrate for the first time that Hg2+ strongly inhibits the function of HRI (IC50=0.6 microM), and nitric oxide fully reverses this inhibition. Other divalent metal cations, such as Fe2+, Cu2+, Cd2+, Zn2+ and Pb2+, also significantly inhibit kinase activity with IC50 values of 1.9-8.5 microM. Notably, inhibition by cations other than Hg2+ is not reversed by nitric oxide. Our present data support dual roles of Hg2+ and nitric oxide in the regulation of protein synthesis during cell emergency states. |
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| Keywords: | HRI, heme-regulated eIF2α kinase or heme-regulated inhibitor eIF2α, α-subunit of eukaryotic initiation factor 2 SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis Fe3+-hemin, Fe3+-protoporphyrin IX complex Fe2+-heme, Fe2+-protoporphyrin IX complex GCN2, general control non-derepressible 2 PKR, pancreatic eIF2α kinase PERK, PKR-like ER kinase TBST, 20 mM Tris-HCl, pH 7.7, 137 mM NaCl containing 1% Tween 20 |
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