MRC National Institute for Medical Research, London
Science for Health
How Mycobacterium tuberculosis copes with its pathogenic lifestyle
23 December 2009
As a consequence of infection by M. tuberculosis, there is an increase in the concentration of the small second-messenger molecule cAMP within the bacterium and also in the macrophage. These high levels of cAMP are known to interfere with host signalling pathways. The levels of cAMP within the bacterium are many times higher than in other bacteria such as Escherichia coli. This high concentration creates its own set of problems, for example with the function of the major bacterial cAMP-responsive protein, the cAMP receptor protein (CRP). This protein controls the expression of a large number of bacterial genes by binding to cAMP. It thereby undergoes allosteric changes that enable it to bind to a specific DNA motif and consequently interact with and recruit the RNA polymerase-sigma factor complex, and thus to activate transcription initiation. In M. tuberculosis this has to occur against the backdrop of very high cAMP levels.
Roger Buxton and colleagues, from Douglas Young's group in NIMR’s Division of Mycobacterial Research, have collaborated with Jeff Green’s lab at the University of Sheffield to study how CRP in M. tuberculosis (CRPMt) manages to control transcription initiation at these high cellular cAMP concentrations. They found that CRPMt has evolved several distinct features. In contrast to CRP from E. coli where cAMP binding enhances specific DNA-binding by several orders of magnitude, cAMP binding to CRPMt is relatively weak resulting in only a small enhancement of DNA-binding. Moreover, at the promoter of the essential whiB1 gene involved in responses to redox changes, they have found that CRPMt acts in a novel way to control transcription through an arrangement of tandem CRP-binding sites situated very close together. One (CRP1) is an activating site whilst a second (CRP2) is a repressing site, only occupied in the presence of cAMP. Intermediate concentrations of cAMP promote binding of CRPMt to CRP1 to activate gene expression, not by the usual mechanism of RNA polymerase recruitment but at a step after open complex formation. In contrast, high cAMP concentrations allow occupation of both sites, resulting in inhibition of open complex formation and of whiB1 gene expression. This arrangement would thus enable whiB1 to be expressed transiently at intermediate levels of cAMP during an infection.
In order to grow within a host, some pathogens manipulate their environment to their own advantage. Mycobacterium tuberculosis is a master of this kind of ecological niche management, allowing it to grow within macrophages, the very cells that have evolved to kill most pathogens. But the changes in metabolism that it causes means that the way in which gene regulation takes place has also had to evolve to cope with these novel conditions. Knowing how M. tuberculosis copes in this way with its peculiar pathogenic lifestyle enables us to identify novel features that may be subject to drug inhibition.
Roger Buxton
Original article
The research findings are published in full in:
Melanie Stapleton, Ihtshamul Haq, Debbie M. Hunt, Kristine B. Arnvig, Peter J. Artymiuk, Roger S. Buxton, and Jeffrey Green (2009)
Mycobacterium tuberculosis cAMP receptor protein (Rv3676) differs from the Escherichia coli paradigm in its cAMP-binding, DNA-binding and transcription activation properties
Journal of Biological Chemistry, epub ahead of print. Publisher abstract
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