Dynamic refolding of IFN-g mRNA enables it to function as PKR activator and translation template
Interferon-g mRNA activates the RNA-dependent protein kinase PKR, which in turn strongly attenuates translation of interferon-g mRNA. Unlike riboswitches restricted to noncoding regions, the interferon-g RNA domain that activates PKR comprises the 5' UTR and 26 translated codons. Extensive inte...
Saved in:
Published in | Nature chemical biology Vol. 5; no. 12; pp. 896 - 903 |
---|---|
Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
01.12.2009
|
Online Access | Get full text |
Cover
Loading…
Summary: | Interferon-g mRNA activates the RNA-dependent protein kinase PKR, which in turn strongly attenuates translation of interferon-g mRNA. Unlike riboswitches restricted to noncoding regions, the interferon-g RNA domain that activates PKR comprises the 5' UTR and 26 translated codons. Extensive interferon-g coding sequence is thus dedicated to activating PKR and blocking interferon-g 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-g mRNA, which is necessary for its dual function as translation template and activator of PKR, and which thus prevents overexpression of this inflammatory cytokine. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 content type line 23 ObjectType-Feature-2 |
ISSN: | 1552-4450 |
DOI: | 10.1038/nchembio.234 |