MicA, a novel protease adaptor in metabolic shutdown.

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We propose to study the way cells can completely transform their identity by activating a 'gene expression switch'. Such transformations are important to naturally maintain health e.g. in embryo development which begins with identical cells which then crucially change into the different types of cells that make up a developed human. Conversely, these transformations can cause harm e.g. when cells become cancerous or pathogens invade hosts. A gene expression switch involves a distinct programme of genetic instruction being deactivated and replaced with an alternative that leads to radical transformation of the cell's nature.In this study my group will examine a newly discovered protein, MicA, which acts an adaptor to the protease ClpC during bacterial spore formation. We have evidence that MicA is involved in metabolic shut-down as the spore becomes dormant. Sporulation is partially responsible for the persistence of 'hospital superbugs' as spores are a long-lived bacterial form, resistant to cleaning agents and thriving in patients depleted of natural gut microflora.We intend to uncover the detailed molecular shapes of MicA when it is free and bound to ClpC using indirect techniques as they are too small to see even using powerful microscopes. We specialise in measuring protein shapes and the way they fit together by producing them artificially in large quantities, with the help of bacteria which act as our 'protein factories'. We then deduce the proteins' molecular structures by processing their behaviour when we bounce X-rays off them or put them in strong magnetic fields. Each of these techniques has its strengths and weaknesses but our combined approach can yield complementary information filling in the gaps left by using just one of the methods. Collaborating with a microbiologist we will feed information into each others' experiments to build up a mechanistic picture of this gene expression switch in bacterial spore formation. For example, if we identify a mutation in one of our proteins that makes it bind more tightly to its partner our collaborator can make the same mutation within bacteria to test whether it has the predicted effect in living systems.By solving this jigsaw puzzle we hope to be in a stronger position to design novel antibiotics to attack the increasing problem of bacterial drug resistance and the project also has longer term implications for understanding metabolism and gene expression switches in many aspects of health and disease.