Targeting and assembly of E. coli division proteins

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DESCRIPTION (provided by applicant): In bacteria such as Escherichia coli, cytokinesis is orchestrated by two essential and highly conserved cytoskeletal proteins: tubulin-like FtsZ and actin-like FtsA. These proteins coassemble into a circumferential polymeric structure, called the Z ring, on the inner membrane at the site of cell division. Once assembled, the ring then recruits a large complex of other proteins to the membrane, probably distributed in individual subcomplexes. This protein machine, often called the divisome, induces synthesis of septal peptidoglycan while constricting at the leading edge of the growing septum, eventually splitting the cell into two. The machine needs to be robust, yet responsive to a variety of inputs, and is therefore overbuilt. This proposal focuses on FtsA and its interactions with FtsZ and with later divisome proteins, because recent results indicate that FtsA regulates assembly of FtsZ, in addition to its role in tethering FtsZ polymers to the membrane and recruiting later divisome components. We hypothesize that FtsA-mediated recycling of FtsZ polymers increases the number of membrane attachment sites for divisome subcomplexes, which stabilizes the machine and maximizes its flexibility. We propose to (i) elucidate how binding of ATP and ADP stimulates FtsA activity and its interaction with FtsZ; (ii) define the molecular contacts between FtsA and FtsZ subunits within FtsZ polymers; and (iii) understand how the FtsZ/FtsA complex interacts with the later divisome subcomplexes. The study of bacterial cell division is important for two reasons. First, it is a basic cellular process that needs to be understood. Second, with the current scarcity of novel antibiotics, the universal and essential process of bacterial cytokinesis is increasingly relevant as a target of antimicrobial drugs. PUBLIC HEALTH RELEVANCE: This project investigates the molecular mechanism of bacterial cell division. The highly conserved proteins in the cell division apparatus represent novel targets for new therapeutics.