A PKR-like eukaryotic initiation factor 2α kinase from zebrafish contains Z-DNA binding domains instead of dsRNA binding domains

Stefan Rothenburg, Nikolaus Deigendesch, Katharina Dittmar, Friedrich Koch-Nolte, Friedrich Haag, Ky Lowenhaupt, Alexander Rich

Research output: Contribution to journalArticle

119 Scopus citations

Abstract

The double-stranded RNA (dsRNA)-dependent protein kinase (PKR) is induced as part of the IFN response in mammals and acts to shut down protein synthesis by the phosphorylation of eukaryotic initiation factor 2α (eIF2α). In fish, a PKR-like kinase activity has been detected, but the enzyme responsible has eluded characterization. Mere, we describe a PKR-like kinase from zebrafish. Phylogenetic analysis shows that the C-terminal kinase domain is more closely related to the kinase domain of PKR than to any of the other three known eIF2α kinases. Surprisingly, instead of the two dsRNA binding domains found at the N terminus of PKR, there are two Zα domains. Zα domains specifically bind dsDNA and RNA in the left-handed Z conformation, often with high affinity. They have been found previously in two other IFN-inducible proteins, the dsRNA editing enzyme, ADAR1, and Z-DNA binding protein 1 (ZBP1), as well as in the poxvirus virulence factor, E3L. This previously undescribed kinase, designated PKZ (protein kinase containing Z-DNA binding domains), is transcribed constitutively at low levels and is highly induced after injection of poly(inosinic)-poly(cytidylic) acid, which simulates viral infection. Binding of Z-DNA by the Zα domain of PKZ was demonstrated by circular dichroism. PKZ inhibits translation in transfected cells; site-directed mutagenesis indicates that this inhibition depends on its catalytic activity. Identification of a gene combining Zα domains with a PKR-like kinase domain strengthens the hypothesis that the ability to bind left-handed nucleic acid plays a role in the host response to viruses.

Original languageEnglish (US)
Pages (from-to)1602-1607
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number5
DOIs
StatePublished - Feb 1 2005
Externally publishedYes

Keywords

  • E3L
  • Interferon response
  • Viral infection
  • Zα domain
  • Z-RNA

ASJC Scopus subject areas

  • General

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