title: Serine cluster phosphorylation liberates the C-terminal helix of IFN regulatory factor 7 to bind histone acetyltransferase p300.
abstract: IFN regulatory factor 7 (IRF7) is a major regulator of type I (αβ) IFN secretion. A growing body of evidence shows that IRF7 is involved in a wide variety of pathologic conditions in addition to infections; however, the detailed mechanism of IRF7 transactivation remains elusive. Our current knowledge of IRF7 transactivation is based on studies of IRF3, another major regulator of IFN-β secretion. IRF3 and IRF7 are closely related homologs with high sequence similarity in their C-terminal regions, and both proteins are activated by phosphorylation of a specific serine cluster (SC). Nevertheless, the functional domains of the two proteins are arranged in an inverted manner. We generated a model structure of the IRF7 C-terminal region using homology modeling and used it to guide subsequent functional domain studies. The model structure led to the identification of a tripod-helix structure containing the SC. Based on the model and experimental data, we hypothesized that phosphorylation-mediated IRF7 transactivation is controlled by a tripod-helix structure. Inducible IκB kinase binds a tripod-helix structure. Serial phosphorylation of the SC by the kinase liberates C-terminal helix from an inhibitory hydrophobic pocket. A histone acetyltransferase P300 binds the liberated helix. The difference in the P300 binding sites explains why the domain arrangement of IRF7 is inverted relative to that of IRF3.
authors.affiliation: Department of Microbiology, University of Ulsan College of Medicine, Seoul 138-736, Korea;
authors.forename: Kyoung Jin
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: Department of Microbiology, University of Ulsan College of Medicine, Seoul 138-736, Korea;
authors.forename: Jung Sook
authors.initials: JS
authors.lastname: Ye
authors.affiliation: Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul 138-736, Korea; Department of Physiology, University of Ulsan College of Medicine, Seoul 138-736, Korea; and.
authors.forename: Han
authors.initials: H
authors.lastname: Choe
authors.affiliation: Department of Microbiology, University of Ulsan College of Medicine, Seoul 138-736, Korea;
authors.forename: Young Ran
authors.initials: YR
authors.lastname: Nam
authors.affiliation: Department of Microbiology, University of Ulsan College of Medicine, Seoul 138-736, Korea;
authors.forename: Nari
authors.initials: N
authors.lastname: Kim
authors.affiliation: Department of Microbiology, University of Ulsan College of Medicine, Seoul 138-736, Korea;
authors.forename: Uk
authors.initials: U
authors.lastname: Lee
authors.affiliation: Department of Microbiology, University of Ulsan College of Medicine, Seoul 138-736, Korea; Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul 138-736, Korea chjoo@amc.seoul.kr.
authors.forename: Chul Hyun
authors.initials: CH
authors.lastname: Joo
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D050839:Interferon Regulatory Factor-7 / Q000737:chemistry / Q000378:metabolism*; D007370:Interferon Type I / Q000096:biosynthesis / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D012694:Serine / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D051550:I-kappa B Kinase; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D012694:Serine; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C494232:IRF3 protein, human; C494234:IRF7 protein, human