Saturday, November 23, 2024
11/23/2024
Project Summary 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 incorrectly exposed hydrophobic regions of proteins or specific tags attached upon prolonged translational arrest. These same machines control levels and dynamics of native folded proteins often through recruiting auxiliary factors to increase selectivity. In this proposed work, we focus on two major energy dependent proteases systems that are conserved in bacteria where understanding of their mechanistic regulation and scope is incomplete. The ClpXP protease selectively degrades major regulators during the Caulobacter cell cycle driven by a dedicated hierarchy adaptors and processes replication factors. Illuminating the molecular details of how adaptors deliver these substrates will reveal rules of specificity crucial for understanding programmed degradation. Similarly, the allosteric regulation of the Lon quality control protease by ligands or substrates is important for its function as a quality control protease, with emerging models suggesting that dynamic conformational changes can modulate specificity. In addition, findings that Lon can selectively remove DNA bound proteins support new regulatory roles for this highly conserved protease. By using proteomics, transposon-sequencing, biochemistry, and genetics to understand how bacteria govern the specificity and activity of these proteases at a mechanistic and cellular level, we will gain critical insight into pathways that control normal growth and stress responses in all bacteria.
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