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: 8303555
• 负责人: WILLIAM MARGOLIN
• 金额: $ 4.3万
• 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/8303555
• 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）： 在细菌（例如大肠杆菌）中，细胞因子由两种必需和高度保守的细胞骨架蛋白精心策划：类似微管蛋白的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汇集成一个称为Z环的圆周聚合结构。组装后，环将招募到膜的大量其他蛋白质，可能分布在单个子复合物中。这种蛋白质机通常称为分裂体，诱导了肽聚糖的隔膜合成，同时在生长的隔膜的前缘收缩，最终将细胞分成两个。该机器需要坚固，但对各种投入都有响应，因此被过度建造。该提案重点介绍了FTSA及其与FTSZ的相互作用以及后来的分裂蛋白，因为最近的结果表明，除了它在将FTSZ聚合物绑定到膜上并募集后来的除法组成分外，FTSA还调节了FTSZ的组装。我们假设FTSA介导的FTSZ聚合物的回收增加了Divisome子复合物的膜附着位点的数量，从而稳定机器并最大程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FTSA和FTSZ亚基之间的分子接触； （iii）了解FTSZ/FTSA复合物如何与后来的Divisome子复合物相互作用。细菌细胞分裂的研究很重要，原因有两个。首先，这是一个基本的蜂窝过程，需要理解。其次，由于当前新型抗生素的稀缺性，细菌细胞因子的普遍和必不可少的过程越来越相关，作为抗菌药物的靶标。 公共卫生相关性： 该项目研究了细菌细胞分裂的分子机制。细胞分裂设备中高度保守的蛋白质代表了新疗法的新靶标。