Regulation and Mechanism of the C. Crescentus Cytokinetic Ring

C. Crescentus细胞动力学环的调控和机制

• 批准号: 9352355
• 负责人: Erin D Goley
• 金额: $ 32万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9352355
• 关键词: Address; Affect; Antibiotics; Bacteria; Binding; Biochemical; Biological; C-terminal; Caulobacter crescentus; Cell Cycle; Cell Polarity; Cell Separation; Cell Wall; Cell division; Cells; Coupled; Cytokinesis; Cytoskeletal Proteins; Defect; Development; Disease; Enzymes; Filament; Generations; Genetic; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Image; In Vitro; Laboratories; Lead; Mediating; Membrane; Metabolic; Metabolism; Modeling; Output; Peptidoglycan; Play; Polymers; Process; Property; Proteins; Proteobacteria; Recruitment Activity; Regulation; Reproduction; Research; Resolution; Role; Site; Stereotyping; Structure; Testing; Time; Translating; Variant; Work; constriction; defined contribution; design; event cycle; functional outcomes; human disease; imaging approach; in vivo; in vivo Model; insight; novel; novel therapeutics; offspring; pathogen; physical property; prevent; public health relevance; scaffold; spatiotemporal; z-ring

 DESCRIPTION (provided by applicant): The faithful execution of cytokinesis is required to produce viable offspring. In bacteria, cytokinesis is orchestrated by the cytoskeletal GTPase, FtsZ. FtsZ polymerizes to form a cytokinetic Z-ring that directs assembly of more than two dozen other factors. Together, the division machinery promotes constriction and fission of the membranes and remodeling of the peptidoglycan (PG) cell wall to ultimately split the cell into two. Despite its conserved and essential function in the majority of bacteria, the precise role of FtsZ in cytokinesis remains poorly defined. In addition to acting as a scaffold, FtsZ is hypothesized to generate constrictive force and/or to regulate PG remodeling. If and how it fulfills these functions in the cell is unknown. Like other cytoskeletal proteins, the assembly properties and structure of FtsZ are central to defining and executing its function. Using genetic, cell biological, biochemical, and advanced imaging approaches, this proposal addresses how three distinct modes of regulating of FtsZ polymer and Z-ring assembly alter its functional output in defined ways in the model bacterium Caulobacter crescentus. Aim 1 addresses how FtsZ polymers are physically targeted to the inner membrane by different tethering proteins to direct FtsZ activity to different functions. Aim 2 focuses on how FtsZ protofilament curvature is used to promote envelope constriction. Aim 3 determines how the disordered C-terminal linker of FtsZ affects its assembly and structure in a manner required for the regulation of PG remodeling enzymes. Successful completion of the proposed research will yield broad insights into the mechanisms of FtsZ function across the bacterial kingdom. Given the essentiality of FtsZ in bacteria, understanding the mechanisms by which it directs growth and division will facilitate its development as a target for novel antibiotics.

 描述（由申请人提供）：胞质分裂是产生可存活后代所必需的。在细菌中，胞质分裂是由细胞骨架 GTP 酶 FtsZ 聚合形成细胞因子 Z 环，指导 20 多个其他分子的组装。分裂机制共同促进细胞膜的收缩和裂变以及肽聚糖 (PG) 细胞壁的重塑，最终将细胞一分为二。尽管 FtsZ 在大多数细菌中具有保守且重要的功能，但其在胞质分裂中的确切作用仍不清楚。除了充当支架外，FtsZ 还被用来产生收缩力和/或调节 PG 重塑。与其他细胞骨架蛋白一样，FtsZ 的组装特性和结构对于定义和执行其功能至关重要。 细胞生物学、生化和先进成像方法，该提案解决了 FtsZ 聚合物和 Z 环组装的三种不同调节模式如何在模型细菌新月柄杆菌中以定义的方式改变其功能输出，目的 1 解决了 FtsZ 聚合物如何物理靶向的问题。通过不同的束缚蛋白将 FtsZ 活性引导至内膜，以引导 FtsZ 活性发挥不同功能。目标 2 重点关注如何利用 FtsZ 原丝曲率来促进包膜。目标 3 确定 FtsZ 的无序 C 末端接头如何以​​调节 PG 重塑酶所需的方式影响其组装和结构。成功完成拟议的研究将为了解 FtsZ 在细菌中的功能机制提供广泛的见解。鉴于 FtsZ 在细菌中的重要性，了解它指导生长和分裂的机制将有助于其作为新型抗生素靶标的开发。