Molecular Mechanisms of Organelle Formation in Bacteria

细菌细胞器形成的分子机制

• 批准号: 10582343
• 负责人: Arash Komeili
• 金额: $ 17.5万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10582343
• 关键词: Actins; Architecture; Area; Bacteria; Biochemical; Biochemical Reaction; Biogenesis; Biological; Biology; Cell membrane; Cells; Chemicals; Contrast Media; Crystallization; Cytoskeleton; Development; Drug Delivery Systems; Environment; Eukaryota; Evolution; Genes; Growth; In Vitro; Individual; Iron; Kinetics; Knowledge; Light; Lipid Bilayers; Lipid Binding; Magnetic Resonance Imaging; Magnetic nanoparticles; Magnetism; Medical; Membrane; Modeling; Molecular; Names; Organelles; Oxygen; Physiological; Process; Protein Dynamics; Protein Sortings; Proteins; Research; Study models; System; Time; Work; base; biomineralization; biophysical properties; delivery vehicle; gut microbiome; magnetosomes; member; membrane biogenesis; microorganism; nanoscale; neoplastic cell; next generation; novel; opportunistic pathogen; particle; physical property; primitive cell; programs; protein function; rational design; targeted delivery; tumor

Project Abstract Lipid-bounded organelles are touted as a defining feature of eukaryotes and one which is absent from the architecturally primitive cells of bacteria. However, numerous bacteria use lipid-bounded organelles to execute essential, and at times toxic, biochemical reactions in a compartmentalized fashion. My group uses the magnetosome organelles of magnetotactic bacteria as a model for understanding the mechanistic basis of organelle formation and function in bacteria. Magnetosomes are lipid-bilayer invaginations of the cell membrane with a unique protein content, within which nanometer-sized iron-based magnetic crystals are produced. Individual magnetosomes are arranged into a chain with the help of an actin-like cytoskeleton, thus allowing magnetotactic bacteria to use geomagnetic fields as a simple guide for low oxygen environments. The cell biological features of magnetosomes make them ideal for understanding the molecular basis of organelle biogenesis in bacteria and, perhaps, uncover the evolutionary origins of eukaryotic organelles. The magnetic and physical properties of magnetosomes make them attractive targets for the development of biomedical applications including their use as contrast agents for magnetic resonance imaging, as drug delivery vehicles and as a medium for hyperthermic killing of tumor cells. In addition to magnetosomes, my group has recently discovered a novel iron-accumulating lipid-bounded organelle named the ferrosome. Ferrosomes are formed through the action of a small number of genes and are found in diverse bacteria including resident members of the gut microbiome and opportunistic pathogens. The research program outlined in this proposal will leverage the expertise and existing knowledge within my group to explore the most critical areas of magnetosome and ferrosome biology. First, we will focus on the cell biological mechanisms that allow for formation and subcellular organization of magnetosomes. We will define the minimal components required for the biogenesis of the magnetosome membrane, uncover the modes and dynamics of protein localization to magnetosomes and study the biochemical and biophysical characteristics of the actin-like cytoskeleton required for organization of magnetosomes. Second, we will investigate the mechanisms of iron biomineralization within magnetosomes. We will uncover the interactions, activity and function of proteins implicated in the nucleation and growth of magnetic particles and will develop simplified in vitro systems to define the kinetics and chemical requirements for biomineralization. Finally, we will use this project period to develop ferrosomes into an alternate and robust model for the study of bacterial organelles. We will determine the mechanisms of ferrosome membrane biogenesis, protein sorting and iron transport and in parallel define their physiological function in relevant microorganisms. The combination of these approaches will shed light on the evolution and mechanistic diversity of bacterial organelles while providing a more rational basis for their use in applied settings.

项目摘要 脂界细胞器被吹捧为真核生物的一个决定性特征，而这是真核生物所不存在的。 细菌的结构原始细胞。然而，许多细菌使用脂质结合的细胞器来执行 以分隔的方式进行必要的、有时是有毒的生化反应。我的小组使用 趋磁细菌的磁小体细胞器作为理解其机制基础的模型 细菌中细胞器的形成和功能。磁小体是细胞的脂质双层内陷 具有独特蛋白质含量的膜，其中纳米尺寸的铁基磁性晶体 产生的。单个磁小体在肌动蛋白样细胞骨架的帮助下排列成链，从而 允许趋磁细菌利用地磁场作为低氧环境的简单引导。这 磁小体的细胞生物学特征使其成为了解细胞器分子基础的理想选择 细菌的生物发生，或许还可以揭示真核细胞器的进化起源。磁性的 磁小体的物理特性使其成为生物医学发展的有吸引力的目标 应用包括用作磁共振成像造影剂、药物输送载体 并作为高温杀死肿瘤细胞的介质。除了磁小体之外，我的团队最近还 发现了一种新型的铁积累脂质结合细胞器，称为铁体。铁体形成 通过少数基因的作用，存在于多种细菌中，包括常驻成员 肠道微生物组和机会病原体。本提案中概述的研究计划将利用 我的团队中探索磁小体最关键领域的专业知识和现有知识 铁体生物学。首先，我们将重点关注允许形成和形成的细胞生物学机制。 磁小体的亚细胞组织。我们将定义生物发生所需的最小成分 磁小体膜，揭示蛋白质定位到磁小体的模式和动力学 并研究肌动蛋白样细胞骨架所需的生化和生物物理特性 磁小体的组织。其次，我们将研究铁生物矿化的机制。 磁小体。我们将揭示成核过程中蛋白质的相互作用、活性和功能 和磁性颗粒的生长，并将开发简化的体外系统来定义动力学和化学 生物矿化的要求。最后，我们将利用这个项目期间将铁体开发成 用于研究细菌细胞器的替代且稳健的模型。我们将确定机制 铁体膜生物发生、蛋白质分选和铁转运，并同时定义了它们的生理学 在相关微生物中发挥作用。这些方法的结合将揭示进化和 细菌细胞器的机械多样性，同时为其在应用中的使用提供更合理的基础 设置。