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Open AccessArticle

MS-Based Approaches Enable the Structural Characterization of Transcription Factor/DNA Response Element Complex

1
Institute of Microbiology, The Czech Academy of Sciences, 14220 Prague, Czech Republic
2
Faculty of Science, Charles University, 12843 Prague, Czech Republic
3
RNA Institute, University at Albany, State University of New York, Albany, NY 12222, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2019, 9(10), 535; https://doi.org/10.3390/biom9100535
Received: 19 July 2019 / Revised: 18 September 2019 / Accepted: 24 September 2019 / Published: 26 September 2019
(This article belongs to the Special Issue Nucleic Acids, Structure and Modeling)
The limited information available on the structure of complexes involving transcription factors and cognate DNA response elements represents a major obstacle in the quest to understand their mechanism of action at the molecular level. We implemented a concerted structural proteomics approach, which combined hydrogen-deuterium exchange (HDX), quantitative protein-protein and protein-nucleic acid cross-linking (XL), and homology analysis, to model the structure of the complex between the full-length DNA binding domain (DBD) of Forkhead box protein O4 (FOXO4) and its DNA binding element (DBE). The results confirmed that FOXO4-DBD assumes the characteristic forkhead topology shared by these types of transcription factors, but its binding mode differs significantly from those of other members of the family. The results showed that the binding interaction stabilized regions that were rather flexible and disordered in the unbound form. Surprisingly, the conformational effects were not limited only to the interface between bound components, but extended also to distal regions that may be essential to recruiting additional factors to the transcription machinery. In addition to providing valuable new insights into the binding mechanism, this project provided an excellent evaluation of the merits of structural proteomics approaches in the investigation of systems that are not directly amenable to traditional high-resolution techniques. View Full-Text
Keywords: transcription factor; protein; DNA; protein-nucleic acid cross-linking; cross-linking; transplatin; trans-dichlorodiamineplatinum(II); hydrogen-deuterium exchange; FOXO4; molecular modeling transcription factor; protein; DNA; protein-nucleic acid cross-linking; cross-linking; transplatin; trans-dichlorodiamineplatinum(II); hydrogen-deuterium exchange; FOXO4; molecular modeling
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Slavata, L.; Chmelík, J.; Kavan, D.; Filandrová, R.; Fiala, J.; Rosůlek, M.; Mrázek, H.; Kukačka, Z.; Vališ, K.; Man, P.; Miller, M.; McIntyre, W.; Fabris, D.; Novák, P. MS-Based Approaches Enable the Structural Characterization of Transcription Factor/DNA Response Element Complex. Biomolecules 2019, 9, 535.

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