title: N-domain-dependent nonphosphorylated STAT4 dimers required for cytokine-driven activation.
abstract: The N-terminal protein interaction domain (N-domain) of the signal transducer and activator of transcription-4 (STAT4) is believed to stabilize interactions between two phosphorylated STAT4 dimers to form STAT4 tetramers. Here, we show that nonphosphorylated STAT4 dimers form in vivo before cytokine receptor-driven activation. Mutations in the N-domain dimerization interface abolished assembly of nonphosphorylated STAT4 dimers and prevented STAT4 phosphorylation mediated by cytokine receptors. In addition, N-domain dimerization occurred for other STAT family members but was homotypic in character. This implies a conserved role for N-domain dimerization, which might include influencing interactions with cytokine receptors, favoring homodimer formation or accelerating formation of the phosphorylated STAT dimer.
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, Missouri 63110, USA.
authors.forename: Naruhisa
authors.initials: N
authors.lastname: Ota
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Brett
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Murphy
authors.forename: Daved H
authors.initials: DH
authors.lastname: Fremont
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D010766:Phosphorylation; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050797:STAT4 Transcription Factor; D015534:Trans-Activators / Q000737:chemistry* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020798:Two-Hybrid System Techniques
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D011994:Recombinant Proteins; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; C494091:Stat4 protein, mouse; D015534:Trans-Activators