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Mechanism of transcription factor recruitment by acidic activators
Södertörn University, School of Life Sciences. Karolinska Institutet.
Södertörn University, School of Life Sciences. Karolinska Institutet.
Stowers Institute for Medical Research, Kansas City, USA.
Stowers Institute for Medical Research, Kansas City, USA.
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2005 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 280, no 23, 21779-21784 p.Article in journal (Refereed) Published
Abstract [en]

Many transcriptional activators are intrinsically unstructured yet display unique, defined conformations when bound to target proteins. Target-induced folding provides a mechanism by which activators could form specific interactions with an array of structurally unrelated target proteins. Evidence for such a binding mechanism has been reported previously in the context of the interaction between the cancer-related c-Myc protein and the TATA-binding protein, which can be modeled as a two-step process in which a rapidly forming, low affinity complex slowly converts to a more stable form, consistent with a coupled binding and folding reaction. To test the generality of the target-induced folding model, we investigated the binding of two widely studied acidic activators, Gal4 and VP16, to a set of target proteins, including TATA-binding protein and the Swi1 and Snf5 subunits of the Swi/Snf chromatin remodeling complex. Using surface plasmon resonance, we show that these activator-target combinations also display bi-phasic kinetics suggesting two distinct steps. A fast initial binding phase that is inhibited by high ionic strength is followed by a slow phase that is favored by increased temperature. In all cases, overall affinity increases with temperature and, in most cases, with increased ionic strength. These results are consistent with a general mechanism for recruitment of transcriptional components to promoters by naturally occurring acidic activators, by which the initial contact is mediated predominantly through electrostatic interactions, whereas subsequent target-induced folding of the activator results in a stable complex.

Place, publisher, year, edition, pages
2005. Vol. 280, no 23, 21779-21784 p.
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:sh:diva-14456DOI: 10.1074/jbc.M502627200ISI: 000229557900015PubMedID: 15826952Scopus ID: 2-s2.0-20444475372OAI: oai:DiVA.org:sh-14456DiVA: diva2:469393
Available from: 2011-12-23 Created: 2011-12-23 Last updated: 2017-06-29Bibliographically approved
In thesis
1. Studies of transcription factor domains and their interactions with other transcription factors
Open this publication in new window or tab >>Studies of transcription factor domains and their interactions with other transcription factors
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The studies in this thesis deal with different questions concerning interactions of functional domains of factors involved in transcriptional regulation. The first study of this thesis is focused on the target factor binding mechanism of transcriptional activators. Many activators in evolutionary distant species are classified as acidic based on a high content of acidic residues in the activation domain and intrinsically unstructured in solution. Our results indicate that such activation domains interact with target factors through coupled binding and folding of the activation domain after an initial ionic interaction, and demonstrate the generality of this binding mechanism. We propose that target interaction through coupled binding and folding of the recruiting domain is important for the role of activators as regulators of transcription. In the following study we show that deletion of two regions that mediate interaction with activators in vitro prevents promoter recruitment of the SWI/SNF chromatinremodeling complex in vivo, and causes strongly reduced transcriptional activity of the corresponding genes. This study validates direct interaction between the Swi1- and Snf5 activator binding domains of the S. cerevisiae SWI/SNF complex and activators previously demonstrated in vitro, and importantly indicates that the activator binding domains are essential for the ability of SWI/SNF to function as co-activator. In the last study we investigate which domains are involved in distinct in vivo function of the paralogous co-repressors Tup11 and Tup12 of the Ssn6/Tup complex in S. pombe. Tup11 and Tup12 have been shown to differ in importance in context of a common complex for subsets of Ssn6/Tup target genes, and it was proposed that this might depend on divergence in the histone-interaction domain. Here we show that distinct in vivo roles of Tup12 do not depend on differences in the highly diverged histoneinteraction domain, but mainly on differences in the overall highly conserved WD40 repeat domain, which putatively mediates interaction with repressors and target factors such as histone modifying complexes and components of the transcriptional machinery. We propose that clusters of amino acids, putatively located in blade 3 of the WD40 repeat domain, could be important for interaction with distinct target factors of Tup11 and Tup12. Furthermore, we show that the stoichiometry of the Ssn6/Tup complex is likely to change under CaCl2 stress, by a mechanism involving changes in the relative cellular levels of the complex components.

Place, publisher, year, edition, pages
Stockholm: Karolinska institutet, 2009. 46 p.
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:sh:diva-31106 (URN)9789174095333 (ISBN)
Public defence
2009-06-11, MB505, Alfred Nobels allé 7, Huddinge, 15:00 (English)
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Supervisors
Available from: 2016-11-09 Created: 2016-11-09 Last updated: 2016-11-09Bibliographically approved

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