Targeting and assembly of E. coli division proteins

大肠杆菌分裂蛋白的靶向和组装

• 批准号: 7888052
• 负责人: WILLIAM MARGOLIN
• 金额: $ 33.57万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7888052
• 关键词: Actins; Address; Affinity; Antibiotics; Bacteria; Binding; Biochemical Genetics; Bypass; Cell division; Cell physiology; Cells; Complex; Contracts; Cytokinesis; Cytoskeletal Proteins; Data; Dimerization; Engineering; Ensure; Escherichia coli; Genes; Goals; Grant; Homologous Gene; In Vitro; Individual; Knowledge; Laboratories; Length; Link; Location; Mechanics; Mediating; Membrane; Modeling; Molecular; Peptidoglycan; Polymers; Positioning Attribute; Process; Proliferating; Protein Conformation; Proteins; Publishing; Recruitment Activity; Recycling; Regulation; Research; Role; Site; Stress; Structure; Time; Tubulin; Work; antimicrobial; antimicrobial drug; base; constriction; experience; flexibility; frontier; insight; interest; mutant; new therapeutic target; novel; operation; public health relevance; response; synthetic construct

DESCRIPTION (provided by applicant): In bacteria such as Escherichia coli, cytokinesis is orchestrated by two essential and highly conserved cytoskeletal proteins: tubulin-like FtsZ and actin-like FtsA. These proteins coassemble into a circumferential polymeric structure, called the Z ring, on the inner membrane at the site of cell division. Once assembled, the ring then recruits a large complex of other proteins to the membrane, probably distributed in individual subcomplexes. This protein machine, often called the divisome, induces synthesis of septal peptidoglycan while constricting at the leading edge of the growing septum, eventually splitting the cell into two. The machine needs to be robust, yet responsive to a variety of inputs, and is therefore overbuilt. This proposal focuses on FtsA and its interactions with FtsZ and with later divisome proteins, because recent results indicate that FtsA regulates assembly of FtsZ, in addition to its role in tethering FtsZ polymers to the membrane and recruiting later divisome components. We hypothesize that FtsA-mediated recycling of FtsZ polymers increases the number of membrane attachment sites for divisome subcomplexes, which stabilizes the machine and maximizes its flexibility. We propose to (i) elucidate how binding of ATP and ADP stimulates FtsA activity and its interaction with FtsZ; (ii) define the molecular contacts between FtsA and FtsZ subunits within FtsZ polymers; and (iii) understand how the FtsZ/FtsA complex interacts with the later divisome subcomplexes. The study of bacterial cell division is important for two reasons. First, it is a basic cellular process that needs to be understood. Second, with the current scarcity of novel antibiotics, the universal and essential process of bacterial cytokinesis is increasingly relevant as a target of antimicrobial drugs. PUBLIC HEALTH RELEVANCE: This project investigates the molecular mechanism of bacterial cell division. The highly conserved proteins in the cell division apparatus represent novel targets for new therapeutics.

描述（由申请人提供）： 在大肠杆菌等细菌中，胞质分裂是由两种必需且高度保守的细胞骨架蛋白精心策划的：微管蛋白样 FtsZ 和肌动蛋白样 FtsA。这些蛋白质在细胞分裂部位的内膜上共同组装成一个圆周聚合结构，称为 Z 环。一旦组装完成，环就会将其他蛋白质的大型复合物招募到膜上，这些蛋白质可能分布在各个子复合物中。这种蛋白质机器，通常称为分裂体，诱导隔膜肽聚糖的合成，同时在生长隔膜的前缘收缩，最终将细胞分裂成两部分。该机器需要坚固耐用，同时又能对各种输入做出响应，因此是过度建造的。该提案重点关注 FtsA 及其与 FtsZ 和后来的分裂体蛋白的相互作用，因为最近的结果表明，FtsA 除了将 FtsZ 聚合物束缚到膜和招募后来的分裂体成分方面的作用之外，还调节 FtsZ 的组装。我们假设 FtsA 介导的 FtsZ 聚合物回收增加了分裂子复合物的膜附着位点数量，从而稳定了机器并最大限度地提高了其灵活性。我们建议 (i) 阐明 ATP 和 ADP 的结合如何刺激 FtsA 活性及其与 FtsZ 的相互作用； (ii) 定义 FtsZ 聚合物内 FtsA 和 FtsZ 亚基之间的分子接触； (iii) 了解 FtsZ/FtsA 复合体如何与后来的分裂子复合体相互作用。细菌细胞分裂的研究很重要，原因有二。首先，这是一个需要理解的基本细胞过程。其次，由于目前新型抗生素的稀缺，细菌胞质分裂的普遍且重要的过程作为抗菌药物的靶标越来越重要。 公共卫生相关性： 该项目研究细菌细胞分裂的分子机制。细胞分裂装置中高度保守的蛋白质代表了新疗法的新靶标。