TY - JOUR
T1 - Dynamic refolding of IFN-γ mRNA enables it to function as PKR activator and translation template
AU - Cohen-Chalamish, Smadar
AU - Hasson, Anat
AU - Weinberg, Dahlia
AU - Namer, Lise Sarah
AU - Banai, Yona
AU - Osman, Farhat
AU - Kaempfer, Raymond
PY - 2009/12
Y1 - 2009/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=73349088152&partnerID=8YFLogxK
U2 - 10.1038/nchembio.234
DO - 10.1038/nchembio.234
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C2 - 19801993
AN - SCOPUS:73349088152
SN - 1552-4450
VL - 5
SP - 896
EP - 903
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 12
ER -