Structure of Proteins Involved in Bacterial Pathogenesis

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Bacterial pathogenesis involves at least two steps: 1- attachment of the bacteria to the host tissue to be infected, and 2- secretion of toxic molecules by the bacteria. Both steps are mediated by a fibrous structure displayed at the surface of the bacteria called a "pilus". On one end of the pilus (facing outwards), the pilus harbours a protein called "adhesin" which binds specifically to the host's surface polysaccharides. On the other end, the pilus may be attached to a secretion machinery responsible for injection of toxic substances. The pilus itself is a complex polymer of several different protein subunits. In this proposal, we propose to study the structural basis of 1- pilus biogenesis, 2- bacterial attachment to the host tissue, and 3-protein secretion. We have used the type P pili of uropathogenic Escherichia coli as a model to study pilus biogenesis and bacterial attachment, and we have used the type IV secretion system of the ulcer-causing Helicobacter pylori as a model to study the secretion of proteins by bacteria. We have obtained several crystals of pilus subunits in complex with their assembly chaperone; we have also crystallized binary complexes of adhesins with their cognate polysaccharides; and finally, we have crystallized important components of the type IV secretion machinery. Two of these structures have been or are in the process of being solved. Our proposal, by seeking to understand the structural basis of pathogenicity in bacteria responsible for important infectious diseases, will have not only an impact on the fundamental knowledge of the various systems under study, but will also help design antibiotic compounds which are effective in the fight against these diseases.