Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

An mRNA structure that controls gene expression by binding S-adenosylmethionine

Nature Structural & Molecular Biology volume 10, pages 701–707 (2003)Cite this article

Abstract

Riboswitches are metabolite-binding RNA structures that serve as genetic control elements for certain messenger RNAs. These RNA switches have been identified in all three kingdoms of life and are typically responsible for the control of genes whose protein products are involved in the biosynthesis, transport or utilization of the target metabolite. Herein, we report that a highly conserved RNA domain found in bacteria serves as a riboswitch that responds to the coenzyme S-adenosylmethionine (SAM) with remarkably high affinity and specificity. SAM riboswitches undergo structural reorganization upon introduction of SAM, and these allosteric changes regulate the expression of 26 genes in Bacillus subtilis. This and related findings indicate that direct interaction between small metabolites and allosteric mRNAs is an important and widespread form of genetic regulation in bacteria.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The S Box is a structured RNA domain that binds SAM.
Figure 2: Binding affinity and molecular discrimination by a SAM-binding RNA.
Figure 3: Scatchard analysis of SAM binding by the yitJ aptamer indicates tight binding and the formation of a 1:1 metabolite–RNA complex.
Figure 4: Effects of RNA mutations on SAM binding and genetic control.
Figure 5: Metabolite-induced transcription termination of several mRNAs that carry a SAM riboswitch.
Figure 6: Bacilli species subtilis and anthracis bind SAM with different affinities.

Similar content being viewed by others

References

  1. Nahvi, A. et al. Genetic control by a metabolite binding mRNA. Chem. Biol. 9, 1043–1049 (2002).

    Article  CAS  Google Scholar 

  2. Winkler, W., Nahvi, A. & Breaker, R.R. Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression. Nature 419, 952–956 (2002).

    Article  CAS  Google Scholar 

  3. Winkler, W.C., Cohen-Chalamish, S. & Breaker, R.R. An mRNA structure that controls gene expression by binding FMN. Proc. Natl. Acad. Sci. USA 99, 15908–15913 (2002).

    Article  CAS  Google Scholar 

  4. Mironov, A.S. et al. Sensing small molecules by nascent RNA: a mechanism to control transcription in bacteria. Cell 111, 747–756 (2002).

    Article  CAS  Google Scholar 

  5. Sudarsan, N., Barrick, J.E. & Breaker, R.R. Metabolite-binding RNA domains are present in the genes of eukaryotes. RNA 644–647 (2003).

  6. Gelfand, M.S., Mironov, A.A., Jomantas, J., Kozlov, Y.I. & Perumov, D.A. A conserved RNA structure element involved in the regulation of bacterial riboflavin synthesis genes. Trends Genet. 15, 439–442 (1999).

    Article  CAS  Google Scholar 

  7. Miranda-Rios, J., Navarro, M. & Soberón, M. A conserved RNA structure (thi box) is involved in regulation of thiamin biosynthetic gene expression in bacteria. Proc. Natl. Acad. Sci. USA 98, 9736–9741 (2001).

    Article  CAS  Google Scholar 

  8. Stormo, G.D. & Ji, Y. Do mRNAs act as direct sensors of small molecules to control their expression? Proc. Natl. Acad. Sci. USA 98, 9465–9467 (2001).

    Article  CAS  Google Scholar 

  9. Rodionov, D.A., Vitreschak, A.G., Mironov, A.A. & Gelfand, M.S. Comparative genomics of thiamin biosynthesis in procaryotes. New genes and regulatory mechanisms. J. Biol. Chem. 277, 48949–48959 (2002).

    Article  CAS  Google Scholar 

  10. Benner, S.A., Ellington, A.D. & Tauer, A. Modern metabolism as a palimpsest of the RNA world. Proc. Natl. Acad. Sci. USA 86, 7054–7058 (1989).

    Article  CAS  Google Scholar 

  11. Joyce, G.F. The antiquity of RNA-based evolution. Nature 418, 214–221 (2002).

    Article  CAS  Google Scholar 

  12. White III, H.B. Coenzymes as fossils of an earlier metabolic state. J. Mol. Evol. 7, 101–104 (1976).

    Article  CAS  Google Scholar 

  13. Jeffares, D.C., Poole, A.M. & Penny, D. Relics from the RNA world. J. Mol. Evol. 46, 18–36 (1998).

    Article  CAS  Google Scholar 

  14. Grundy, F.J. & Henkin, T.M. The S box regulon: a new global transcription termination control system for methionine and cysteine biosynthesis genes in Gram-positive bacteria. Mol. Microbiol. 30, 737–749 (1998).

    Article  CAS  Google Scholar 

  15. Henkin, T.M. Transcription termination control in bacteria. Curr. Opin. Microbiol. 3, 149–153 (2000).

    Article  CAS  Google Scholar 

  16. Grundy, F.J. & Henkin, T.M. The T box and S box transcription termination control systems. Frontiers Biosci. 8, D20–31 (2003).

    Article  CAS  Google Scholar 

  17. Soukup, G.A. & Breaker, R.R. Relationship between internucleotide linkage geometry and the stability of RNA. RNA 5, 1308–1325 (1999).

    Article  CAS  Google Scholar 

  18. Gold, L., Poliski, B., Uhlenbeck, O.C. & Yarus, M. Diversity of oligonucleotide functions. Annu. Rev. Biochem. 64, 763–797 (1995).

    Article  CAS  Google Scholar 

  19. Takusagawa, F., Fujioka, M., Spies, A. & Schowen, R.L. In Comprehensive Biological Catalysis Vol. 1 (ed. Sinnott, M.) 1–30 (Academic, New York, 1998).

    Google Scholar 

  20. McDaniel, B.A.M., Grundy, F.J., Artsimovitch, I. & Henkin, T.M. Transcription termination control of the S box system: direct measurement of S-adenosylmethionine by the leader RNA. Proc. Natl. Acad. Sci. USA 100, 3083–3088 (2003).

    Article  CAS  Google Scholar 

  21. Posnick, L.M. & Samson, L.D. Influence of S-adenosylmethionine pool size on spontaneous mutation, dam methylation, and cell growth of Escherichia coli. J. Bacteriol. 181, 6756–6762 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Epshtein, V., Mironov, A.S. & Nudler, E. The riboswitch-mediated control of sulfur metabolism in bacteria. Proc. Natl. Acad. Sci. USA 100, 5052–5056 (2003).

    Article  CAS  Google Scholar 

  23. Mansilla, M.C., Albanesi, D. & De Mendoza, D. Transcriptional control of the sulfur-regulated cysH operon, containing genes involved in L-cysteine biosynthesis in Bacillus subtilis. J. Bacteriol. 182, 5885–5892 (2000).

    Article  CAS  Google Scholar 

  24. Mandal, M., Boese, B., Barrick, J.E., Winkler, W.C. & Breaker, R.R. Metabolite-sensing riboswitches control fundamental biochemical pathways in bacteria. Cell 113, 577–586 (2003).

    Article  CAS  Google Scholar 

  25. Seetharaman, S., Zivartz, M., Sudarsan, N. & Breaker, R.R. Immobilized RNA switches for the analysis of complex chemical and biological mixtures. Nat. Biotechnol. 19, 336–341 (2001).

    Article  CAS  Google Scholar 

  26. Guérout-Fleury, A.M., Frandsen, N. & Stragier, P. Plasmids for ectopic integration in Bacillus subtilis. Gene 180, 57–61 (1996).

    Article  Google Scholar 

  27. Fersht, A. In Structure and Mechanism in Protein Science 113 (Freeman, New York, 1999).

    Google Scholar 

  28. Jarmer, H., Berka, R., Knudsen, S. & Saxild, H.H. Transcriptome analysis documents induced competence of Bacillus subtilis during nitrogen limiting conditions. FEMS Microbiol. Lett. 206, 197–200 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J.K. Wickiser for assistance with the Scatchard analysis, other members of the Breaker laboratory for helpful discussions, and D. Söll at Yale University for the generous gift of B. subtilis strain 168. We also thank A. Miranker and B. Koo for assistance in confirming the purity of SAM using mass spectroscopy. This work was supported by grants from the US National Institutes of Health and the US National Science Foundation. R.R.B is also grateful for support from the David and Lucile Packard Foundation.

Author information

Authors and Affiliations

  1. Department of Molecular, Cellular and Developmental Biology, Yale University, PO Box 208103, New Haven, 06520-8103, Connecticut, USA

    Wade C Winkler, Narasimhan Sudarsan & Ronald R Breaker

  2. Department of Molecular Biophysics and Biochemistry, Yale University, PO Box 208103, New Haven, 06520-8103, Connecticut, USA

    Ali Nahvi & Jeffrey E Barrick

Authors
  1. Wade C Winkler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ali Nahvi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Narasimhan Sudarsan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeffrey E Barrick
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ronald R Breaker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ronald R Breaker.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Winkler, W., Nahvi, A., Sudarsan, N. et al. An mRNA structure that controls gene expression by binding S-adenosylmethionine. Nat Struct Mol Biol 10, 701–707 (2003). https://doi.org/10.1038/nsb967

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsb967

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing