The research to be performed for this application will increase understanding of bacterial cell division. Although cell division is one of the most basic biological processes, there is relatively little known about what each component of the subcellular cell division machinery does and how the entire process is regulated. For this work the model organism Escherichia coli will be used. This organism is ideal for the study of cell division because (1) much about the basic genetics and cell biology of this organism is already known;(2) excellent genetic tools are available;and (3) the basic protein components of cell division in E. coli are highly conserved in other bacterial species. When a cell is about to divide, an essential protein called FtsZ polymerizes into a ring-like structure known as the Z ring at the center of the cell. Numerous other proteins, many of them also essential, are recruited to the Z ring. One of these proteins is FtsA. The ftsZ and ftsA genes are one of the most highly conserved bacterial gene pairs. Some of the activities of FtsA are known, but the molecular roles of FtsA remain elusive. The current line of thought is that FtsA regulates the formation of the Z ring by two mechanisms. First, FtsA tethers the ring to the inner membrane of the cell, connecting the Z ring to inner membrane proteins. Second, FtsA regulates the disassembly of the Z ring, so that it will constrict and divide the cell. The current data suggest that membrane binding, self-interaction and nucleotide binding are all critical for FtsA function and that each of these properties can be correlated to each other. Mutations that inhibit any one of these FtsA activities seem to affect FtsA-FtsZ interactions, which prevents normal cell division. The research proposed here will (1) determine how FtsA membrane binding and self-association are correlated and (2) define how each of these activities determines the ability of FtsA to affect the Z ring. Because they share some of the same properties, FtsA and MinC may affect FtsZ through analogous mechanisms. The study of bacterial cell division is important because it is a basic cellular process that needs to be understood and because it is a highly relevant target for potentially new antimicrobial drugs.
When bacterial cells cannot divide, they cannot multiply and spread. In this time of increasing bacterial resistance to antibiotic treatments it is critical that we decipher the mechanisms that allow these populations to proliferate. Understanding the mechanism of bacterial cell division will provide more targets for new antimicrobial therapeutics.
| Herricks, Jennifer R; Nguyen, Diep; Margolin, William (2014) A thermosensitive defect in the ATP binding pocket of FtsA can be suppressed by allosteric changes in the dimer interface. Mol Microbiol 94:713-27 |
