Regulated Proteolysis in Bacteria Development and Stress Response

细菌发育和应激反应中的调节蛋白水解

• 批准号: 10321913
• 负责人: Peter Chien
• 金额: $ 37.98万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321913
• 关键词: Antibiotics; Bacteria; Biochemical Genetics; Cell Cycle Progression; DNA Damage; Development; Growth and Development function; Hydrophobicity; Molecular; Morphology; Pathway interactions; Peptide Hydrolases; Process; Protein Region; Proteins; Proteolysis; Quality Control; Role; Specificity; System; Virulence; Work; biological adaptation to stress; endopeptidase La; genetic approach; human pathogen; insight; protein folding

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.

项目摘要。 受调节的蛋白质水解控制蛋白质的质量和数量。在细菌中，能量依赖蛋白酶 通过识别由质量控制失败引起的独特标记来消除异常蛋白质，例如 蛋白质的不适当暴露的疏水区域或在长时间翻译后附着的特异性标签 逮捕了这些相同的机器还控制完全活性的、折叠良好的蛋白质的水平和动力学， 适当地管理从细胞周期进展到DNA损伤的分子过程。在此提出的 工作，我们将集中在两个主要的蛋白酶系统，发现整个细菌，是至关重要的 人类病原体的毒力。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， 生化和遗传策略。第二，我们将揭示长期以来以其在蛋白质合成中的作用而闻名的Lon蛋白酶是如何在蛋白质合成中发挥作用的。 蛋白质质量控制，调节胁迫反应和形态变化的建设，使用系统水平 接近。通过破译细菌如何控制这些蛋白酶的特异性和活性， 机制和细胞水平，我们将获得关键的洞察到一个途径，可以有针对性的急需 新的抗生素策略