Crystal structure of IRF-3 reveals mechanism of autoinhibition and virus-induced phosphoactivation.
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.
Qin
Bin Y
BY
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester 01605, USA.
Liu
Cheng
C
Lam
Suvana S
SS
Srinath
Hema
H
Delston
Rachel
R
Correia
John J
JJ
Derynck
Rik
R
Lin
Kai
K
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D050838:Interferon Regulatory Factor-3; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D055672:Static Electricity; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D014157:Transcription Factors; D011494:Protein Kinases