Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression

Abstract

Although proteins fulfil most of the requirements that biology has for structural and functional components such as enzymes and receptors, RNA can also serve in these capacities. For example, RNA has sufficient structural plasticity to form ribozyme1,2 and receptor3,4 elements that exhibit considerable enzymatic power and binding specificity. Moreover, these activities can be combined to create allosteric ribozymes5,6 that are modulated by effector molecules. It has also been proposed7,8,9,10,11,12 that certain messenger RNAs might use allosteric mechanisms to mediate regulatory responses depending on specific metabolites. We report here that mRNAs encoding enzymes involved in thiamine (vitamin B1) biosynthesis in Escherichia coli can bind thiamine or its pyrophosphate derivative without the need for protein cofactors. The mRNA–effector complex adopts a distinct structure that sequesters the ribosome-binding site and leads to a reduction in gene expression. This metabolite-sensing regulatory system provides an example of a ‘riboswitch’ whose evolutionary origin might pre-date the emergence of proteins.

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Figure 1: Metabolite binding by mRNAs.
Figure 2: The thiM and thiC mRNA leaders serve as high-affinity metabolite receptors.
Figure 3: High sensitivity and selectivity of mRNA leaders for metabolite binding.
Figure 4: Mutational analysis of the structure and function of the thiM riboswitch.
Figure 5: Schematic representation of the proposed mechanism for TPP-dependent deactivation of thiM translation.

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Acknowledgements

We thank members of the Breaker laboratory for comments on the manuscript, especially N. Sudarsan for discussions. This work was supported by the NIH and the NSF, and by a fellowship to R.R.B. from the David and Lucile Packard Foundation.

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Correspondence to Ronald R. Breaker.

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The authors declare that they have no competing financial interests.

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Winkler, W., Nahvi, A. & Breaker, R. Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression. Nature 419, 952–956 (2002). https://doi.org/10.1038/nature01145

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