Professor of Biochemistry and Molecular Biology, University of Massachusetts
Ph.D.: University of California, San Francisco Postdoctoral Training: MIT
Regulated proteolysis controls the quality and quantity of proteins. In bacteria, energy dependent proteases eliminate aberrant proteins by recognizing distinctive marks arising from failed quality control, such as inappropriately exposed hydrophobic regions of proteins or specific tags attached upon prolonged translational arrest. These same machines also control levels and dynamics of fully active, well-folded proteins in order to properly manage molecular processes ranging from cell cycle progression to DNA damage. The goal of my lab is to understand how regulated proteolysis shapes both normal and stress responses in bacteria. We use (i) reconstitution biochemistry with highly purified proteins to investigate enzymatic activity and structure-function relationships, (ii) proteomics to investigate proteome dynamics and identify novel protease substrates, and (iii) genomics to determine global outcomes in transcription and gene-gene interactions upon changes in protease capacity.
Our rationale for exploring regulated bacterial proteases is straightforward. First, we are genuinely curious how proteolysis contributes to the biology of bacteria. In many cases, bacteria growth is sufficiently rapid that dilution of proteins upon cell division sustains protein dynamics. However, during acute stress responses or development, bacteria must change their proteomes without division and proteolysis plays a major role in protein dynamics. To explore this basic curiosity driven question we use the model bacteria Caulobacter crescentus as it undergoes obligate differentiation upon every cell division. Second, we firmly believe that regulated proteases are underexplored antibiotic targets as they are required for virulence in every human pathogen where these machines have been investigated. To this end, we are also exploring the protease specificities from bacteria such as Vibrio cholera (causative agent of cholera) and Borrelia burgdorferi (causative agent of Lyme disease) while performing small molecule screens to identify chemical modulators of proteases as potential candidates for novel antibiotics.