The faithful execution of cytokinesis is required to produce viable offspring. In bacteria, cytokinesis is orchestrated by the cytoskeletal GTPase, FtsZ. FtsZ polymerizes to form a cytokinetic Z-ring that directs assembly of more than two dozen other factors. Together, the division machinery promotes constriction and fission of the membranes and remodeling of the peptidoglycan (PG) cell wall to ultimately split the cell into two. Despite its conserved and essential function in the majority of bacteria, the precise role of FtsZ in cytokinesis remains poorly defined. In addition to acting as a scaffold, FtsZ is hypothesized to generate constrictive force and/or to regulate PG remodeling. If and how it fulfills these functions in the cell is unknown. Like other cytoskeletal proteins, the assembly properties and structure of FtsZ are central to defining and executing its function. Using genetic, cell biological, biochemical, and advanced imaging approaches, this proposal addresses how three distinct modes of regulating of FtsZ polymer and Z-ring assembly alter its functional output in defined ways in the model bacterium Caulobacter crescentus.
Aim 1 addresses how FtsZ polymers are physically targeted to the inner membrane by different tethering proteins to direct FtsZ activity to different functions.
Aim 2 focuses on how FtsZ protofilament curvature is used to promote envelope constriction.
Aim 3 determines how the disordered C-terminal linker of FtsZ affects its assembly and structure in a manner required for the regulation of PG remodeling enzymes. Successful completion of the proposed research will yield broad insights into the mechanisms of FtsZ function across the bacterial kingdom. Given the essentiality of FtsZ in bacteria, understanding the mechanisms by which it directs growth and division will facilitate its development as a target for novel antibiotics.
This proposal aims to understand how bacterial cells divide, a process that is required for successful reproduction. Most bacteria, including almost all of those that cause human diseases, use the same essential machinery to accomplish cell division. Understanding how the molecules that divide the bacterial cell work may lead to identification of new targets for antibiotic development and facilitate rational design of new drugs.
