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DNA binding reduces the dissociation rate of STAT1 dimers and impairs the interdimeric exchange of protomers

BACKGROUND: A shift between two dimer conformations has been proposed for the transcription factor STAT1 (signal transducer and activator of transcription 1) which links DNA binding of the parallel dimer to tyrosine dephosphorylation of the antiparallel dimer as two consecutive and important steps i...

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Autores principales: Riebeling, Theresa, Staab, Julia, Herrmann-Lingen, Christoph, Meyer, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284922/
https://www.ncbi.nlm.nih.gov/pubmed/25526807
http://dx.doi.org/10.1186/s12858-014-0028-z
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author Riebeling, Theresa
Staab, Julia
Herrmann-Lingen, Christoph
Meyer, Thomas
author_facet Riebeling, Theresa
Staab, Julia
Herrmann-Lingen, Christoph
Meyer, Thomas
author_sort Riebeling, Theresa
collection PubMed
description BACKGROUND: A shift between two dimer conformations has been proposed for the transcription factor STAT1 (signal transducer and activator of transcription 1) which links DNA binding of the parallel dimer to tyrosine dephosphorylation of the antiparallel dimer as two consecutive and important steps in interferon- γ (IFNγ)-mediated signalling. However, neither the kinetics nor the molecular mechanisms involved in this conformational transition have been determined so far. RESULTS: Our results demonstrated that the dissociation of dimers into monomers and their subsequent re-association into newly formed tyrosine-phosphorylated dimers is a relatively slow process as compared to the fast release from high-affinity DNA-binding sites, termed GAS (gamma-activated sequence). In addition, we noted an inhibitory effect of GAS binding on the exchange rate of protomers, indicating that DNA binding substantially impedes the recombination of dimeric STAT1. Furthermore, we found that reciprocal aminoterminal interactions between two STAT1 molecules are not required for the interchange of protomers, as an oligomerization-deficient point mutant displayed similar interdimeric exchange kinetics as the wild-type molecule. CONCLUSIONS: Our results demonstrate that DNA binding impairs the oscillation rate between STAT1 conformers. Furthermore, these data suggest that the rapid release from high-affinity GAS sites is not a rate-limiting step in IFNγ-mediated signal transduction. Further investigations are needed to decipher the physiological significance of the observed dissociation/re-association process of STAT1 dimers.
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spelling pubmed-42849222015-01-07 DNA binding reduces the dissociation rate of STAT1 dimers and impairs the interdimeric exchange of protomers Riebeling, Theresa Staab, Julia Herrmann-Lingen, Christoph Meyer, Thomas BMC Biochem Research Article BACKGROUND: A shift between two dimer conformations has been proposed for the transcription factor STAT1 (signal transducer and activator of transcription 1) which links DNA binding of the parallel dimer to tyrosine dephosphorylation of the antiparallel dimer as two consecutive and important steps in interferon- γ (IFNγ)-mediated signalling. However, neither the kinetics nor the molecular mechanisms involved in this conformational transition have been determined so far. RESULTS: Our results demonstrated that the dissociation of dimers into monomers and their subsequent re-association into newly formed tyrosine-phosphorylated dimers is a relatively slow process as compared to the fast release from high-affinity DNA-binding sites, termed GAS (gamma-activated sequence). In addition, we noted an inhibitory effect of GAS binding on the exchange rate of protomers, indicating that DNA binding substantially impedes the recombination of dimeric STAT1. Furthermore, we found that reciprocal aminoterminal interactions between two STAT1 molecules are not required for the interchange of protomers, as an oligomerization-deficient point mutant displayed similar interdimeric exchange kinetics as the wild-type molecule. CONCLUSIONS: Our results demonstrate that DNA binding impairs the oscillation rate between STAT1 conformers. Furthermore, these data suggest that the rapid release from high-affinity GAS sites is not a rate-limiting step in IFNγ-mediated signal transduction. Further investigations are needed to decipher the physiological significance of the observed dissociation/re-association process of STAT1 dimers. BioMed Central 2014-12-20 /pmc/articles/PMC4284922/ /pubmed/25526807 http://dx.doi.org/10.1186/s12858-014-0028-z Text en © Riebeling et al.; licensee BioMed Central. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Riebeling, Theresa
Staab, Julia
Herrmann-Lingen, Christoph
Meyer, Thomas
DNA binding reduces the dissociation rate of STAT1 dimers and impairs the interdimeric exchange of protomers
title DNA binding reduces the dissociation rate of STAT1 dimers and impairs the interdimeric exchange of protomers
title_full DNA binding reduces the dissociation rate of STAT1 dimers and impairs the interdimeric exchange of protomers
title_fullStr DNA binding reduces the dissociation rate of STAT1 dimers and impairs the interdimeric exchange of protomers
title_full_unstemmed DNA binding reduces the dissociation rate of STAT1 dimers and impairs the interdimeric exchange of protomers
title_short DNA binding reduces the dissociation rate of STAT1 dimers and impairs the interdimeric exchange of protomers
title_sort dna binding reduces the dissociation rate of stat1 dimers and impairs the interdimeric exchange of protomers
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284922/
https://www.ncbi.nlm.nih.gov/pubmed/25526807
http://dx.doi.org/10.1186/s12858-014-0028-z
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