Mechanisms and Regulation of Cell Division in Bacteria

细菌细胞分裂的机制和调控

• 批准号: 10373994
• 负责人: WILLIAM MARGOLIN
• 金额: $ 42.76万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373994
• 关键词: Actins; Address; Anabolism; Antibiotics; Bacteria; Bacterial Model; Biomimetics; Biophysics; Bypass; Cell Wall; Cell division; Cell physiology; Cells; Cities; Collaborations; Cues; Cytokinesis; Cytology; Escherichia coli; Genetic Materials; Growth; Image; In Vitro; Infrastructure; Investigation; Maps; Membrane Proteins; Microscopy; Molecular Genetics; Polymers; Proliferating; Protein Biochemistry; Proteins; Public Health; Regulation; Resistance; Resolution; Role; Structure; System; Time; Tubulin; Work; cell growth; flexibility; genetic approach; insight; medical specialties; nanomachine; new therapeutic target; novel; reconstitution; response; success

Project summary A cell is like a city, with an organized yet dynamic infrastructure grouped into specialties. For the last 25 years, my lab has investigated how the simplest cells—bacteria—organize themselves and divide to make progeny cells. We mainly focus on how bacteria such as E. coli achieve the daunting task of splitting themselves in two at just the right time (once their genetic material is duplicated) and place (exactly in the middle) every 20 minutes without making errors. The keys to this success are ancient and universal versions of protein polymers of actin (FtsA) and tubulin (FtsZ), which our lab visualized for the first time in living bacteria over 20 years ago. Today, we use state of the art super-resolution imaging, combined with molecular genetics, protein biochemistry, interaction studies, and in vitro reconstitution, to gain more detailed insights into the structure and regulation of these cytoskeletal polymers and their associated proteins, which comprise the dynamic membrane-associated protein nanomachine (divisome) that divides bacterial cells. Thanks in part to our characterization of bypass suppressors of essential divisome proteins, it is now becoming clear that the divisome is highly flexible, and can remodel itself in response to various inputs and perturbations. Despite impressive contributions by many labs, there is much to be learned about overall divisome structure, the interchangeability of its parts, and how it remodels in response to temporal and environmental cues. We will address these fundamental questions by (1) obtaining more high-resolution information about protein-protein contacts during cytokinesis by combining biophysical, cytological, and genetic approaches; (2) investigating the role of oligomeric state of FtsZ and FtsA in divisome function and regulation, using super-resolution microscopy of whole cells and reconstituted biomimetic protein-membrane systems; (3) taking advantage of the diversity of divisome proteins from other model bacterial species to distinguish between common and specialized mechanisms; (4) understanding the interplay between the divisome and other large-scale cellular processes such as cell wall biosynthesis. We will leverage these approaches by continuing our collaborations with several close colleagues who have complementary interdisciplinary expertise. Our ongoing investigation of how the simplest cells divide should pave the way for an unprecedented understanding of how an entire cell functions and reproduces. Having an accurate map of that city-cell's dynamic infrastructure will allow predictions to be made about how it works, and how to disrupt it.

项目摘要 一个牢房就像一个城市，有一个有组织但动态的基础设施分为专业。为了 最近25年，我的实验室调查了最简单的细胞（细菌）如何组织自己和 划分以使进度细胞。我们主要关注大肠杆菌等细菌如何实现 艰巨的任务是在适当的时间分为两个（一旦他们的遗传材料是） 复制）和每20分钟（恰好位于中间），而不会犯错。关键 这种成功是肌动蛋白（FTSA）和微管蛋白的古老而通用的版本 （FTSZ），我们的实验室在20年前的活细菌中首次对其进行了可视化。今天，我们使用 最先进的超分辨率成像，结合分子遗传学，蛋白质生物化学， 相互作用研究和体外重构，以获得对结构和 调节这些细胞骨架聚合物及其相关蛋白，其中包括 动态膜相关的蛋白纳米机械（分裂），该蛋白纳米机构分裂细菌细胞。 一定程度地感谢我们对基本分裂蛋白的旁路补充剂的特征，这是 现在越来越清楚地表明，分裂体是高度灵活的，并且可以对 各种输入和扰动。尽管许多实验室做出了令人印象深刻的贡献，但还有很多要 了解整体分裂结构，零件的互换性以及如何重塑 响应临时和环境提示。我们将通过 （1）在细胞因子过程中获得有关蛋白质 - 蛋白质接触的更多高分辨率信息 结合生物物理，细胞学和遗传方法； （2）调查寡聚的作用 通过使用超分辨率显微镜检查，FTSZ和FTSA的状态 全细胞和重建的仿生蛋白质膜系统； （3）利用 除其他模型细菌种类的分裂蛋白的多样性以区分常见 和专业机制； （4）理解分裂体与其他人之间的相互作用 大规模的细胞过程，例如细胞壁生物合成。我们将通过 继续我们与几个具有完整性的密切合作的合作 跨学科专业知识。 我们正在进行的对最简单单元格的调查应为如何铺平道路 对整个细胞的功能和再现的前所未有的理解。有准确的 该城市电池的动态基础架构的地图将允许对其运作方式做出预测， 以及如何破坏它。