An integrated study of a bacterial secretion nanomachine. (360G-Wellcome-098302_Z_12_Z)

For this proposal, the major question is the following: how do type IV secretion (T4S) systems work? T4S systems are very large, multicomponent, macromolecular complexes embedded in the membranes of bacteria. They are used to secrete virulence proteins and DNAs, and play essential roles in bacterial pathogenesis. To answer our central question, we will use a combination of structural, biochemical, and cell microbiological approaches to fulfil the following objectives: 1- To determine the struct ure of a T4S system. 2- To dissect the molecular basis of substrate recruitment by T4S systems and to determine the structure of a T4S system bound to its substrate. 3- To capture and determine the structures of functional states leading to substrate export and release. 4- To test mechanisms of T4S system-mediated transport. 5- To establish the mechanism of assembly of T4S systems. 6- To use our knowledge of the secretion mechanism to design novel T4S system inhibitors.