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Characterization of Mycobacterium tuberculosis Rv3676 (CRP_Mt), a Cyclic AMP Receptor Protein-Like DNA Binding Protein

Wadsworth Center, New York State Department of Health, 120 New Scotland Avenue, P.O. Box 22002, Albany, New York 12201-2002,¹ Department of Biomedical Sciences, University at Albany, Albany, New York 12222²

Received 10 June 2005/ Accepted 29 August 2005

Little is known about cyclic AMP (cAMP) function in Mycobacterium tuberculosis, despite its ability to encode 15 adenylate cyclases and 10 cNMP-binding proteins. M. tuberculosis Rv3676, which we have designated CRP_Mt, is predicted to be a cAMP-dependent transcription factor. In this study, we characterized CRP_Mt's interactions with DNA and cAMP, using experimental and computational approaches. We used Gibbs sampling to define a CRP_Mt DNA motif that resembles the cAMP receptor protein (CRP) binding motif model for Escherichia coli. CRP_Mt binding sites were identified in a total of 73 promoter regions regulating 114 genes in the M. tuberculosis genome, which are being explored as a regulon. Specific CRP_Mt binding caused DNA bending, and the substitution of highly conserved nucleotides in the binding site resulted in a complete loss of binding to CRP_Mt. cAMP enhanced CRP_Mt's ability to bind DNA and caused allosteric alterations in CRP_Mt conformation. These results provide the first direct evidence for cAMP binding to a transcription factor in M. tuberculosis, suggesting a role for cAMP signal transduction in M. tuberculosis and implicating CRP_Mt as a cAMP-responsive global regulator.

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