Abstract
IRF-3, a member of the interferon regulatory factor (IRF) family of transcription factors, functions as a molecular switch for antiviral activity. IRF-3 uses an autoinhibitory mechanism to suppress its transactivation potential in uninfected cells, and virus infection induces phosphorylation and activation of IRF-3 to initiate the antiviral responses. The crystal structure of the IRF-3 transactivation domain reveals a unique autoinhibitory mechanism, whereby the IRF association domain and the flanking autoinhibitory elements condense to form a hydrophobic core. The structure suggests that phosphorylation reorganizes the autoinhibitory elements, leading to unmasking of a hydrophobic active site and realignment of the DNA binding domain for transcriptional activation. IRF-3 exhibits marked structural and surface electrostatic potential similarity to the MH2 domain of the Smad protein family and the FHA domain, suggesting a common molecular mechanism of action among this superfamily of signaling mediators.
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Acknowledgements
We thank J. Qing for generating the expression plasmid for GST-fused IRF-3 and B. Chacko for critical reading of the manuscript. We thank the staff members of Advanced Light Source for assistance with the data collection of IRF-3 crystals. This research was supported by grants from the US National Institutes of Health to K.L and R.D.
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Qin, B., Liu, C., Lam, S. et al. Crystal structure of IRF-3 reveals mechanism of autoinhibition and virus-induced phosphoactivation. Nat Struct Mol Biol 10, 913–921 (2003). https://doi.org/10.1038/nsb1002
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DOI: https://doi.org/10.1038/nsb1002
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