Regulated Proteolysis in Bacteria Development and Stress Response

Project Summary.Regulated proteolysis controls the quality and quantity of proteins. In bacteria, energy dependent proteaseseliminate aberrant proteins by recognizing distinctive marks arising from failed quality control, such asinappropriately exposed hydrophobic regions of proteins or specific tags attached upon prolonged translationalarrest. These same machines also control levels and dynamics of fully active, well-folded proteins in order toproperly manage molecular processes ranging from cell cycle progression to DNA damage. In this proposedwork, we will focus on two major proteases systems that are found throughout bacteria and are crucial forvirulence in human pathogens. First, we will determine how a newly discovered adaptor hierarchy controls thedelivery of key proteins to the ClpXP protease during bacteria development and growth using structural,biochemical and genetic strategies. Second, we will uncover how the Lon protease, long known for its role inprotein quality control, regulates stress responses and morphological changes building using systems-levelapproaches. By deciphering how bacteria govern the specificity and activity of these proteases at amechanistic and cellular level, we will gain critical insight into a pathway that can be targeted by much needednew antibiotic strategies.