Pseudosubstrate inhibition of protein kinase PKR by swine pox virus C8L gene product.
The interferon-induced protein kinase PKR is activated upon binding double-stranded RNA and phosphorylates the translation initiation factor eIF2alpha on Ser-51 to inhibit protein synthesis in virally infected cells. Swinepox virus C8L and vaccinia virus K3L gene products structurally resemble the amino-terminal third of eIF2alpha. We demonstrate that the C8L protein, like the K3L protein, can reverse the toxic effects caused by high level expression of human PKR in yeast cells. In addition, expression of either the K3L or C8L gene product was found to reverse the inhibition of reporter gene translation caused by PKR expression in mammalian cells. The inhibitory function of the K3L and C8L gene products in these assays was found to be critically dependent on residues near the carboxyl-termini of the proteins including a sequence motif shared among eIF2alpha and the C8L and K3L gene products. Thus, despite significant sequence differences both the C8L and K3L proteins function as pseudosubstrate inhibitors of PKR.
Kawagishi-Kobayashi
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Laboratory of Eukaryotic Gene Regulation, National Institute of Child Health and Human Development, Bethesda, Maryland, 20892-2716, USA.
Cao
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Lu
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Ozato
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Dever
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D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D004791:Enzyme Inhibitors / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005786:Gene Expression Regulation; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D014176:Protein Biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D018148:Suipoxvirus / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism
C415770:C8L protein, Swinepox virus; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; D014764:Viral Proteins; C081646:pK3 protein, Vaccinia virus; D008156:Luciferases; D019892:eIF-2 Kinase