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NMR Structural Profiling of Transcriptional Intermediates Reveals Riboswitch Regulation by Metastable RNA Conformations

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Institute for Organic Chemisty and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ), Johann Wolfgang Goethe-Universität, Frankfurt/M. 60438, Germany
‡ § Department of Theoretical Chemistry and §Faculty of Computer Science, Research Group Bioinformatics and Computational Biology, University of Vienna, 1090 Vienna, Austria
Medical University of Vienna, Center for Anatomy and Cell Biology, Währingerstraße 13, 1090 Vienna, Austria
Cite this: J. Am. Chem. Soc. 2017, 139, 7, 2647–2656
Publication Date (Web):January 30, 2017
Copyright © 2017 American Chemical Society
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Abstract Image

Gene repression induced by the formation of transcriptional terminators represents a prime example for the coupling of RNA synthesis, folding, and regulation. In this context, mapping the changes in available conformational space of transcription intermediates during RNA synthesis is important to understand riboswitch function. A majority of riboswitches, an important class of small metabolite-sensing regulatory RNAs, act as transcriptional regulators, but the dependence of ligand binding and the subsequent allosteric conformational switch on mRNA transcript length has not yet been investigated. We show a strict fine-tuning of binding and sequence-dependent alterations of conformational space by structural analysis of all relevant transcription intermediates at single-nucleotide resolution for the I-A type 2′dG-sensing riboswitch from Mesoplasma florum by NMR spectroscopy. Our results provide a general framework to dissect the coupling of synthesis and folding essential for riboswitch function, revealing the importance of metastable states for RNA-based gene regulation.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.6b10429.

  • NMR characterization of the antiterminator conformation, detailed secondary structure screening of transcriptional intermediates, effect of Mg2+ on the antiterminator conformation, simulations of cotranscriptional folding, transcription assays, and ITC data of transcriptional intermediates (PDF)

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This article is cited by 28 publications.

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  3. Fengfei Wang, Li-Zhen Sun, Tingting Sun, Shan Chang, Xiaojun Xu. Helix-Based RNA Landscape Partition and Alternative Secondary Structure Determination. ACS Omega 2019, 4 (13) , 15407-15413.
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  13. César Parra-Rojas, Boris Fürtig, Harald Schwalbe, Esteban A. Hernandez-Vargas. Quantitative modeling of the function of kinetically driven transcriptional riboswitches. Journal of Theoretical Biology 2020, 506 , 110406.
  14. Anita Kotar, Hannah N. Foley, Kirk M. Baughman, Sarah C. Keane. Advanced approaches for elucidating structures of large RNAs using NMR spectroscopy and complementary methods. Methods 2020, 183 , 93-107.
  15. Osama Alaidi, Fareed Aboul‐ela. Statistical mechanical prediction of ligand perturbation to RNA secondary structure and application to riboswitches. Journal of Computational Chemistry 2020, 41 (16) , 1521-1537.
  16. Yuying Sun, Yanli Wang, Zhi-Jie Tan, Wenbing Zhang. Regulation mechanism of lysC riboswitch in gram-positive bacterium Bacillus subtilis. Journal of Biomolecular Structure and Dynamics 2020, 38 (9) , 2784-2791.
  17. Robbin Schnieders, Sara Keyhani, Harald Schwalbe, Boris Fürtig. More than Proton Detection—New Avenues for NMR Spectroscopy of RNA. Chemistry – A European Journal 2020, 26 (1) , 102-113.
  18. Marie Teng-Pei Wu, Victoria D’Souza. Alternate RNA Structures. Cold Spring Harbor Perspectives in Biology 2020, 12 (1) , a032425.
  19. Huaqun Zhang, Sarah C. Keane. Advances that facilitate the study of large RNA structure and dynamics by nuclear magnetic resonance spectroscopy. WIREs RNA 2019, 10 (5)
  20. Laura R. Ganser, Megan L. Kelly, Daniel Herschlag, Hashim M. Al-Hashimi. The roles of structural dynamics in the cellular functions of RNAs. Nature Reviews Molecular Cell Biology 2019, 20 (8) , 474-489.
  21. Stefan Hammer, Christian Günzel, Mario Mörl, Sven Findeiß. Evolving methods for rational de novo design of functional RNA molecules. Methods 2019, 161 , 54-63.
  22. Jasleen Kaur Bains, Julius Blechar, Vanessa de Jesus, Nathalie Meiser, Heidi Zetzsche, Boris Fürtig, Harald Schwalbe, Martin Hengesbach. Combined smFRET and NMR analysis of riboswitch structural dynamics. Methods 2019, 153 , 22-34.
  23. Christina Helmling, Dean-Paulos Klötzner, Florian Sochor, Rachel Anne Mooney, Anna Wacker, Robert Landick, Boris Fürtig, Alexander Heckel, Harald Schwalbe. Life times of metastable states guide regulatory signaling in transcriptional riboswitches. Nature Communications 2018, 9 (1)
  24. Michael T. Wolfinger, Christoph Flamm, Ivo L. Hofacker. Efficient computation of co-transcriptional RNA-ligand interaction dynamics. Methods 2018, 143 , 70-76.
  25. Judith Schlagnitweit, Emilie Steiner, Hampus Karlsson, Katja Petzold. Efficient Detection of Structure and Dynamics in Unlabeled RNAs: The SELOPE Approach. Chemistry - A European Journal 2018, 24 (23) , 6067-6070.
  26. Anne-Marie Dussault, Audrey Dubé, Frédéric Jacques, Jonathan P. Grondin, Daniel A. Lafontaine. Ligand recognition and helical stacking formation are intimately linked in the SAM-I riboswitch regulatory mechanism. RNA 2017, 23 (10) , 1539-1551.
  27. Hannah Steinert, Florian Sochor, Anna Wacker, Janina Buck, Christina Helmling, Fabian Hiller, Sara Keyhani, Jonas Noeske, Steffen Grimm, Martin M Rudolph, Heiko Keller, Rachel Anne Mooney, Robert Landick, Beatrix Suess, Boris Fürtig, Jens Wöhnert, Harald Schwalbe. Pausing guides RNA folding to populate transiently stable RNA structures for riboswitch-based transcription regulation. eLife 2017, 6
  28. Christopher P. Jones, Adrian R. Ferré-D'Amaré. Long-Range Interactions in Riboswitch Control of Gene Expression. Annual Review of Biophysics 2017, 46 (1) , 455-481.

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