Interferon-γ mRNA activates the RNA-dependent protein kinase PKR, which in turn strongly attenuates translation of interferon-γ mRNA. Unlike riboswitches restricted to noncoding regions, the interferon-γ RNA domain that activates PKR comprises the 5′ UTR and 26 translated codons. Extensive interferon-γ coding sequence is thus dedicated to activating PKR and blocking interferon-γ synthesis. This implies that the PKR activator is disrupted by ribosomes during translation initiation and must refold promptly to restore PKR activation. The activator structure harbors an essential kink-turn, probably to allow formation of a pseudoknot that is critical for PKR activation. Three indispensable short helices, bordered by orientation-sensitive base pairs, align with the pseudoknot stem, generating RNA helix of sufficient length to activate PKR. Through gain-of-function mutations, we show that the RNA activator can adopt alternative conformations that activate PKR. This flexibility promotes efficient refolding of interferon-γ mRNA, which is necessary for its dual function as translation template and activator of PKR, and which thus prevents overexpression of this inflammatory cytokine.
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Dynamic refolding of IFN-γ mRNA enables it to function as PKR activator and translation template
Cohen-Chalamish, Smadar; Hasson, Anat; Weinberg, Dahlia; Namer, Lise Sarah; Banai, Yona; Osman, Farhat; Kaempfer, Raymond
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, Volume 5 (12)
Nature Publishing Group (NPG) – Oct 4, 2009
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