The long-term objectives of this research are to determine the molecular mechanisms involved in bacterial cell division and the underlying spatial and temporal regulatory mechanisms. Our efforts have focused on the FtsZ protein which assembles into a cytoskeletal ring that recruits other proteins to the division site and directs cell division in bacteria. Recent work has shown that FtsZ is a structural and functional homologue of the eukaryotic cytoskeletal protein tubulin. Like tubulin FtsZ undergoes dynamic assembly that is regulated by GTP hydrolysis. Also, FtsZ is a target of several inhibitors that regulate cell division in bacteria. Recent work has shown that SulA and MinC are inhibitors of FtsZ assembly. SulA is induced in response to DNA damage and MinC is part of the division site selection system. In the present proposal biochemical and genetic studies are designed to determine the mechanism of action of these inhibitors. At present SulA is thought to sequester FtsZ monomers and MinC is thought to destabilize FtsZ polymers. Our present studies should further define the interaction between FtsZ and these inhibitors to test the postulated mechanisms. Also, several aspects of MinC's mode of action will be investigated including its interaction with MinD and MinE, which cause it to oscillate between the poles of the cell. In addition, studying the various mutant FtsZs should reveal additional aspects of FtsZ assembly. The present proposal will also examine the interaction between FtsZ and ZipA and FtsA. Genetic and biochemical experiments are proposed to investigate the interacting surfaces between these proteins and the role of these proteins in FtsZ assembly. FtsZ mutants that will be isolated will serve as controls for in vitro experiments. Additional ftsZ(Ts) mutations will be isolated and used to look for suppressors in an attempt to find other proteins that regulate FtsZ assembly. Research over the past few years has shown that FtsZ is a universal feature of bacterial cell division. It has great similarity to tubulin but is also quite distinct. As a result it should prove to be a useful, novel target for antimicrobial therapy.
Showing the most recent 10 out of 64 publications
