Nature Structural Biology10, 913 - 921 (2003)
Published online: 12 October 2003; | doi:10.1038/nsb1002
Crystal structure of IRF-3 reveals mechanism of autoinhibition and virus-induced phosphoactivation
Bin Y Qin1, 4, Cheng Liu2, 4, Suvana S Lam1, Hema Srinath1, Rachel Delston2, John J Correia3, Rik Derynck2
& Kai Lin1
1
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
2
Departments of Growth and Development, and Anatomy, Programs in Cell Biology and Developmental Biology, University of California at San Francisco, San Francisco, California 94143-0640, USA.
3
Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
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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