Crystal structure of IRF-3 reveals mechanism of autoinhibition and virus-induced phosphoactivation

• DOI: 10.1038/nsb1002
• Publication Date: 2003-10-12T18:36:15Z
• Authors: Bin Y Qin; Cheng Liu; Suvana S Lam; Hema Srinath; Rachel Delston; John J Correia; Rik Derynck; Kai Lin
• Keywords: 0303 health sciences; Molecular Sequence Data; Static Electricity; Crystallography, X-Ray; Protein Structure, Tertiary; 3. Good health; DNA-Binding Proteins; 03 medical and health sciences; Humans; Interferon Regulatory Factor-3; Amino Acid Sequence; Phosphorylation; Protein Kinases; Sequence Alignment; Transcription Factors

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.