Controlling the Elongasome: Exploring protein complex formation in the bacterial protein complex responsible for cell shape.

The determination of cell shape and its relationship to cell division is a fundamental question in biology. In bacteria, a major component of this process is provided by the essential extracellular polymer peptidoglycan (PG), which is a mesh-like sacculus surrounding the cytoplasmic membrane and is composed of polymerized glycan chains, cross-linked by short peptides. Disruption of PG biosynthesis results in cell lysis or cessation of growth, making it a major target for antibiotics. This is exploited as an Achilles's heel by many natural product antibiotics as well semisynthetic drugs including the beta-lactams, the most clinically successful antibiotics to date. Whilst there is wide recognition of these factors from a basic biology and translational medicine perspective, the coordination of the events that lead to the formation of PG remains an area where knowledge is critically lacking, particularly at a molecular level of detail. The proteins that participate in PG synthesis, from the cytoplasmic enzymes that synthesize the precursor Lipid II to the extracellular enzymes that are responsible for its polymerisation, have been individually characterized biochemically and structurally. However, increasing evidence suggests that many if not most of these enzymes function in vivo as part of a multi-protein complex "machine" which facilitates rapid and efficient PG synthesis. In this project we will be focusing on a subset of proteins collectively termed the elongasome that are responsible for the determination of cell shape. Informed by structural and bioinformatic information, we are examining the way in which this protein complex assembles and affects the way in which the elongasome assembles the peptidoglycan layer in bacteria. The goal of this project is to understand at a molecular level how the organization of this biosynthetic complex facilitates optimal pathway function and thus cell shape and growth.