Helicobacter pylori is a carcinogenic bacterial pathogen that chronically infects more than half of the global human population and is a risk factor for the development of stomach cancer in a subset of those infected. It is contracted primarily during childhood and can persist for decades if left untreated. H. pylori colonization is facilitated by a postulated corkscrew mechanism that enables the bacteria to escape the inhospitable acidic lumen, traverse through the viscous mucus lining of the stomach and intimately associate with the epithelial surface of the stomach. Non-helical H. pylori mutants are defective for efficient colonization and our lab has identified many proteins that contribute to normal helical cell shape. These cell-shape-determinant (Csd) proteins modify the bacterial cell wall through direct and indirect actions on peptidoglycan (PG); PG is a singular molecule that encases the cell and which determines the shape of nearly all bacteria. My overarching hypothesis states that during growth, Csd proteins must be localized in both time and space to modify the peptidoglycan in a way that generates the asymmetrical helical morphology characteristic of H. pylori. I will take a multidisciplinary approach to solving this four dimensional problem by coupling structural, biochemical and evolutionary analyses of two proteins that likely function in concert to promote helical cell shape. I will investigate the molecular determinants of Csd4 and Csd5 function and investigate a direct protein-protein interaction between them. I will employ domain deletion studies, quantitative cell shape and molecular evolutionary analyses to test our hypothesis that the non-enzymatic Csd5 protein orchestrates localized modification of PG to generate the helical asymmetry. My long term goal is to unify our understanding of the interplay between all of the known and yet to be discovered Csd proteins in H. pylori.