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1. Hüntelmann, Bettina. Molekulare Determinanten zur sequenzspezifischen DNA-Bindung des Transkriptionsfaktors STAT1.

Degree: PhD, Medizinische Fakultät, 2018, Georg-August-Universität Göttingen

STAT proteins (signal transducers and activators of transcription) play an essential part in one of the oldest and highly conserved signal transduction pathways. The JAK-STAT pathway transmits signals from many cytokines arriving at the plasma membrane to the cell nucleus, resulting in a modulation of gene expression. STATs are involved in a variety of processes such as cell growth and immune responses. A key feature in gene induction by STAT proteins is the binding to specific palindrome sequences, known as gamma activated sites (GAS). Since the exact mechanisms of signal dependent target recognition by tyrosine phosphorylated STAT have not yet been thoroughly investigated, directed mutagenesis was used in this study to introduce point mutations in the STAT1 linker and DNA-binding domain. The resulting mutants were characterized functionally. Results showed that three critical amino acid residues in the STAT1 linker domain (E559, E563 and K567) are located in a homologous sequence pattern which is highly conserved among the seven STAT human proteins. Furthermore, these superficially exposed residues are located in close proximity to the bound DNA helix. Substitution of the conserved lysine residue at position 567 resulted in a loss of specific binding to high affinity GAS sites, as well as a complete lack in the transactivation of IFNγ-regulated endogenous target genes. However, the time course of transient nuclear accumulation and tyrosine phosphorylation did not differ from the kinetics of the wild-type molecule. These results demonstrated that the lysine residue at position 567 of the STAT1 linker do-main is required for GAS recognition. In addition, two glutamic acid residues at position E559 and E563 are important for the dissociation of the STAT1 dimer from DNA. The substitution of the glutamic acid residues led to an increased rate of tyrosine phosphorylation as well as prolonged cytokine-stimulated nuclear accumulation in IFNγ-treated cells. The point mutant K350A in the STAT1 DNA-binding domain did not provide any further information about molecular mechanisms of signal-dependent target gene recognition, since the mutant did not differ from the wild type protein. In conclusion, the data confirm the impact of the linker domain on signal-dependent GAS binding mediated by the steric arrangement of the glutamic acid residues E559 and E563 located on the inner surface of the STAT1 dimer. The two glutamic acid residues are aligned perpendicular to the DNA on the longitudinal axis of the STAT1 dimer. By this arrangement, the residues seem to facilitate the interaction between the lysine residue 567 and the phosphodiester backbone of the bound GAS element, thereby establishing the prerequisite for transient gene induction.

STAT-Proteine (Signaltransduktor und Aktivator der Transkription) haben eine essentielle Rolle in einem der ältesten und hochkonservierten Signaltransduktionswege, dem JAK-STAT-Signaltransduktionsweg. Sie leiten die an der Plasmamembran ankommenden Signale vieler Zytokine bis in…

Advisors/Committee Members: Meyer, Thomas (advisor), Meyer, Thomas (referee), Kube, Dieter (referee).

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APA (6th Edition):

Hüntelmann, B. (2018). Molekulare Determinanten zur sequenzspezifischen DNA-Bindung des Transkriptionsfaktors STAT1. (Doctoral Dissertation). Georg-August-Universität Göttingen. Retrieved from http://hdl.handle.net/11858/00-1735-0000-002E-E319-6

Chicago Manual of Style (16th Edition):

Hüntelmann, Bettina. “Molekulare Determinanten zur sequenzspezifischen DNA-Bindung des Transkriptionsfaktors STAT1.” 2018. Doctoral Dissertation, Georg-August-Universität Göttingen. Accessed October 22, 2018. http://hdl.handle.net/11858/00-1735-0000-002E-E319-6.

MLA Handbook (7th Edition):

Hüntelmann, Bettina. “Molekulare Determinanten zur sequenzspezifischen DNA-Bindung des Transkriptionsfaktors STAT1.” 2018. Web. 22 Oct 2018.

Vancouver:

Hüntelmann B. Molekulare Determinanten zur sequenzspezifischen DNA-Bindung des Transkriptionsfaktors STAT1. [Internet] [Doctoral dissertation]. Georg-August-Universität Göttingen; 2018. [cited 2018 Oct 22]. Available from: http://hdl.handle.net/11858/00-1735-0000-002E-E319-6.

Council of Science Editors:

Hüntelmann B. Molekulare Determinanten zur sequenzspezifischen DNA-Bindung des Transkriptionsfaktors STAT1. [Doctoral Dissertation]. Georg-August-Universität Göttingen; 2018. Available from: http://hdl.handle.net/11858/00-1735-0000-002E-E319-6

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