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J Mol Biol. 2009 Dec 11;394(4):591-9. doi: 10.1016/j.jmb.2009.10.033. Epub 2009 Oct 21.

Bicarbonate-mediated stimulation of RegA, the global virulence regulator from Citrobacter rodentium.

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Department of Microbiology and Immunology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia.


The global virulence regulatory protein RegA, an AraC-like regulator, controls the expression of more than 60 genes in the mouse enteric pathogen Citrobacter rodentium. In the presence of bicarbonate, RegA activates the transcription of a number of virulence determinants and inhibits the expression of a series of housekeeping genes. To elucidate the molecular mechanism by which bicarbonate stimulates RegA activity, we carried out biophysical and mutational analyses. Our data indicate that RegA exists as a dimer in solution regardless of bicarbonate concentration. A leucine zipper, located in the region downstream of the N-terminal domain, is responsible for dimerisation. The N-terminal arm itself is involved in modulating the response to bicarbonate, which appears to bind to a region comprising a series of beta-sheets within the N-terminal domain. The presence of bicarbonate relieves the autoinhibition of RegA activity by its N-terminal arm. RegA is the first example of a bacterial virulence regulator that utilises the light switch mechanism, previously described for the Escherichia coli AraC protein, to respond to a gut-associated effector that controls its activity.

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