All organisms require a class of cellular machinery termed ATP-dependent proteases that are responsible for the highly regulated removal of misfolded or properly folded proteins in cellular quality control pathways. These machines are conceptually similar to paper shredders, where material is fed into an interior compartment and shredded. On the molecular level, ATP-dependent proteases are responsible for recognizing specific proteins or polypeptides and “shredding” them through a process called proteolysis. In bacteria, ATP-dependent proteases are assembled from two components that include an adenosine triphosphate (ATP)-fueled motor and an associated protease that catalyzes protein/polypeptide degradation. In the assembled ATP-dependent protease complex, the motor component uses the energy of ATP hydrolysis to thread polypeptide substrates into the protease for degradation. Due to their vital role in maintaining cellular health, inhibition of any component of the ATP-dependent protease complex may serve as a viable route to the development of novel therapeutics to infections caused by pathogenic bacteria.
Research in the Miller laboratory focuses on furthering our understanding of ATP-dependent proteases from pathogenic bacteria. We combine physical biochemistry methods such as fluorescence spectroscopy, pre-steady state kinetics, coupled-enzyme assays, etc. with other disciplines that include organic chemistry and evolutionary biology with the goal of understanding how motor proteins recognize and translocate protein substrates into the associated protease for degradation. This knowledge is important because it will advance our mission towards the development of drug molecules designed to interfere with normal proteolytic function. A central philosophy of the Miller lab is that if we can understand how these proteins function, we can then devise novel approaches to disrupting their function in pathogenic bacteria.