Regulated Proteolysis in Bacteria Development and Stress Response

项目摘要。 受调控的蛋白质降解作用控制蛋白质的质量和数量。在细菌中，依赖能量的蛋白酶 通过识别因质量控制失败而产生的特殊标记来消除异常蛋白质，例如 不适当暴露的蛋白质疏水区或长时间翻译后附着的特定标签 逮捕。这些机器还控制完全活跃的、折叠良好的蛋白质的水平和动态，以便 妥善管理从细胞周期进展到DNA损伤的分子过程。在本建议中 ，我们将重点研究在细菌中发现的两个主要的蛋白水解酶系统，它们对 人类病原体的毒性。首先，我们将确定新发现的适配器层次结构如何控制 在细菌发育和生长过程中，利用Structure， 生化和遗传策略。其次，我们将揭开Lon蛋白水解酶是如何 蛋白质质量控制，使用系统级调节应激反应和形态变化构建 接近了。通过破译细菌是如何控制这些蛋白酶的特异性和活性的 机械和细胞水平，我们将获得关键的洞察力的途径，可以作为目标的迫切需要 新的抗生素策略。

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 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. In this proposed work, we will focus on two major proteases systems that are found throughout bacteria and are crucial for virulence in human pathogens. First, we will determine how a newly discovered adaptor hierarchy controls the delivery 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 in protein quality control, regulates stress responses and morphological changes building using systems-level approaches. By deciphering how bacteria govern the specificity and activity of these proteases at a mechanistic and cellular level, we will gain critical insight into a pathway that can be targeted by much needed new antibiotic strategies.