title: Consequences of the disease-related L78R mutation for dimerization and activity of STAT3.
abstract: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is centrally involved in diverse processes including haematopoiesis, immunity and cancer progression. In response to cytokine stimulation, STAT3 is activated through phosphorylation of a single tyrosine residue. The phosphorylated STAT3 dimers are stabilized by intermolecular interactions between SH2 domains and phosphotyrosine. These activated dimers accumulate in the nucleus and bind to specific DNA sequences, resulting in target gene expression. We analysed and compared the structural organizations of the unphosphorylated latent and phosphorylated activated STAT3 dimers using Förster resonance energy transfer (FRET) in fixed and living cells. The latent dimers are stabilized by homotypic interactions between the N-terminal domains. A somatic mutation (L78R) found in inflammatory hepatocellular adenoma (IHCA), which is located in the N-terminal domain of STAT3 disturbs latent dimer formation. Applying intramolecular FRET, we verify a functional role of the SH2 domain in latent dimer formation suggesting that the protomers in the latent STAT3 dimer are in a parallel orientation, similar to activated STAT3 dimers but different from the antiparallel orientation of the latent dimers of STAT1 and STAT5. Our findings reveal unique structural characteristics of STAT3 within the STAT family and contribute to the understanding of the L78R mutation found in IHCA.
authors.affiliation: Institut für Biochemie und Molekularbiologie, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Tamás
authors.initials: T
authors.lastname: Domoszlai
authors.forename: Antons
authors.initials: A
authors.lastname: Martincuks
authors.forename: Dirk
authors.initials: D
authors.lastname: Fahrenkamp
authors.forename: Hildegard
authors.initials: H
authors.lastname: Schmitz-Van de Leur
authors.forename: Andrea
authors.initials: A
authors.lastname: Küster
authors.forename: Gerhard
authors.initials: G
authors.lastname: Müller-Newen
mesh_terms: D015153:Blotting, Western; D031541:Fluorescence Resonance Energy Transfer; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D009154:Mutation; D010766:Phosphorylation; D055503:Protein Multimerization; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor
keywords: Dimerization; FRET; Fluorescence microscopy; Hyper-IgE syndrome; Inflammatory hepatocellular adenoma; JAK-STAT signalling; STAT3