Stress response pathways
Stress response pathways, such as the general stress response pathway, play important roles in bacterial virulence. In the model Gram-negative bacterium, Escherichia coli the general stress response pathway is regulated by the transcription factor, SigmaS. The activity of which, is controlled not only at the transcriptional and translational level but also at the level of protein stability. Under normal cellular conditions, SigmaS is rapidly degraded by the protease ClpXP, but only in the presence of the adaptor protein RssB. Interestingly, the activity of RssB is regulated not only by phosphorylation, but also by several "stress inducible" proteins (e.g. IraD, which responds to DNA damage) known as anti-adaptors.
Currently, we are dissecting the molecular details of the interaction between SigmaS and RssB, and its delivery to ClpXP. We are also interested in the mechanism of inhibition of the various different anti-adaptor proteins. Developing a detailed understanding of these interactions could provide the opportunity to develop novel antibiotics against pathogenic bacteria.
Our group is also interested in the role of several related mitochondrial proteases (LONM, ClpXP and m-AAA) and how these proteins contribute to stress response pathways in humans, such as the mitochondrial unfolded protein response. These projects are performed in collaboration with Dr Kaye Truscott.