Stress related proteases in Caulobacter crescentus

新月柄杆菌中应激相关的蛋白酶

• 批准号: 9119126
• 负责人: Peter Chien
• 金额: $ 29.09万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9119126
• 关键词: Address; Affect; Antibiotics; Bacteria; Beryllium; Binding; Biochemical Genetics; Biological; Caulobacter; Caulobacter crescentus; Cell Cycle Arrest; Cell Cycle Regulation; Cells; Characteristics; Client; Complex; DNA Damage; DNA biosynthesis; Development; Elements; Employee Strikes; Environment; Escherichia coli; Genetic Transcription; Growth; Health; Human; In Vitro; Invaded; Kinetics; Link; Modeling; Molecular Chaperones; Nucleotides; Pathogenicity; Pathway interactions; Peptide Hydrolases; Peptides; Play; Process; Production; Protein Isoforms; Proteins; Proteolysis; Proteomics; Quality Control; Resources; Rest; Role; Signal Transduction; Slide; Stress; Testing; Virulence; Work; biological adaptation to stress; endopeptidase La; improved; in vivo; insight; novel; pathogen; prevent; protein degradation; protein folding; protein misfolding; repaired; response; stress tolerance

DESCRIPTION (provided by applicant): Bacteria use energy dependent proteases to respond to stressful conditions. These proteases serve a dual role: destroying aberrant, potentially toxic, damaged proteins and generating stress responsive signals through degradation of regulatory factors. Cells often arrest replication in response to stress, but how regulated proteolysis contributes to cell cycle arrest in bacteria is currently poorly understood. This proposal addresses how stress related proteases target replication factors using a combination of biochemical, genetic and proteomic approaches, specifically focusing on proteases and replication factors from the model bacteria Caulobacter crescentus. Aims 1 and 2 determine how misfolded proteins generated during proteotoxic stress directly stimulate the Lon protease to destroy the replication initiator DnaA and cause growth arrest during stress. Aims 3 and 4 focus on how partial processing of the clamp loader subunit DnaX by the ClpXP protease is critical for replication stress tolerance during DNA damage. Because these proteases and replication factors are highly conserved throughout all bacteria, these results will impact our general understanding of replication, proteolysis, and stress tolerance. The critical role of these proteases in bacterial virulence and pathogenicity, together with the universal requirement for these proteases in bacterial stress responses, suggests that they are excellent targets for development of new antibiotic strategies that are of immediate human health need.

描述（由申请人提供）：细菌利用能量依赖性蛋白酶来应对应激条件。这些蛋白酶具有双重作用：破坏异常的、潜在有毒的、 受损的蛋白质并通过调节因子的降解产生应激反应信号。细胞通常会因应激而抑制复制，但目前人们对调节蛋白水解如何导致细菌细胞周期停滞知之甚少。该提案解决了压力相关蛋白酶如何结合生化、遗传和蛋白质组学方法来靶向复制因子，特别关注来自模型细菌新月柄杆菌的蛋白酶和复制因子。目标 1 和 2 确定蛋白毒性应激期间产生的错误折叠蛋白如何直接刺激 Lon 蛋白酶破坏复制起始子 DnaA 并导致应激期间生长停滞。目标 3 和 4 重点关注 ClpXP 蛋白酶对夹钳装载机亚基 DnaX 的部分处理对于 DNA 损伤期间的复制应激耐受性至关重要。由于这些蛋白酶和复制因子在所有细菌中高度保守，因此这些结果将影响我们对复制、蛋白水解和应激耐受性的一般理解。这些的关键作用 蛋白酶在细菌毒力和致病性中的作用，以及细菌应激反应中对这些蛋白酶的普遍需求，表明它们是开发人类健康迫切需要的新抗生素策略的极好目标。