Energy Transduction Between Membranes

膜之间的能量转换

• 批准号: 7462610
• 负责人: KATHLEEN POSTLE
• 金额: $ 45.22万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7462610
• 关键词: Active Biological Transport; Address; Affinity; Antibiotics; Area; Biochemical; Cell membrane; Cells; Chemicals; Communicable Diseases; Complex; Conflict (Psychology); Cytoplasmic Tail; Data; Development; Diffusion; Energy-Generating Resources; Escherichia coli; Failure; Future; Goals; Gram-Negative Bacteria; Harvest; In Vitro; Iron; Knowledge; Maintenance; Maps; Mechanics; Membrane; Membrane Transport Proteins; Modeling; Modification; Molecular; Molecular Conformation; Movement; Mutation; Nutrient; Play; Proteins; Public Health; Role; Siderophores; Site; Structure; System; Virulence; Virulent; Vitamin B 12; Work; base; cell motility; human TYRP1 protein; in vivo; novel; pathogen; periplasm; prevent; uptake

DESCRIPTION (provided by applicant): The outer membranes of Gram-negative bacteria are barriers to diffusion of certain nutrients into the periplasmic space and subsequent transport into the cell. To acquire large, scarce, important nutrients such as iron-siderophores and vitamin B12, active transporters with sub-nanomolar affinities for their transport substrates are located in the outer membrane. Because the outer membrane lacks a conventional energy source, energy for active transport of iron-siderophores and vitamin B12 across the outer membrane and into the periplasmic space derives from the protonmotive force of the cytoplasmic membrane. The TonB-ExbB-ExbD system in the cytoplasmic membrane appears to harvest protonmotive force and transduce it in an unknown form to the outer membrane active transporters. Our long-term goal is to understand the mechanism of TonB-dependent energy transduction between the cytoplasmic and outer membranes of Escherichia coli. Mutations in tonB render many species significantly less virulent. Due to the role that iron availability plays in infectious disease, it is widely recognized the TonB system has potential as a novel target for the development of new antibiotics. Additional significance arises from our ability to contribute to a broad understanding of energy transduction mechanisms in general. There are currently no paradigms for TonB-dependent energy transduction and yet based on homologies, there are at least three such systems that transduce the pmf into useful work in virtually all Gram-negative bacteria. Besides the ExbB/D proteins, there are the TolQ/R proteins (required for OM integrity) and the MotA/B proteins (required for motility). Our results will therefore also contribute importantly to basic knowledge of the other energy transduction systems as broad principles emerge. As Specific Aims, we will address three fundamental problems in the TonB system: What are the determinants of TonB energization at the cytoplasmic membrane, what form of energy is transduced to the outer membrane transporters, and how does a transporter become energized by TonB? PUBLIC HEALTH RELEVANCE: Virtually all Gram negative bacteria use the TonB system to circumvent the limitations to iron acquisition posed by their outer membranes. Understanding of the molecular mechanism by which the TonB system energizes transport across the outer membranes will allow future development of new antibiotics that prevent iron uptake. The ability of pathogens to acquire iron is an important virulence determinant in infectious disease.

描述（由申请人提供）：革兰氏阴性细菌的外膜是将某些营养物质扩散到周质空间并随后转运到细胞中的障碍。为了获得大量，稀缺，重要的营养素，例如铁螺体和维生素B12，其运输底物具有亚纳摩尔亲和力的活性转运蛋白位于外膜。由于外膜缺乏常规的能源，因此铁 - 辅助载体和维生素B12在整个外膜和周围空间中主动运输的能量源自细胞质膜的质子力力。细胞质膜中的TONB-EXBB-EXBD系统似乎会收集质子敏化力，并以未知形式转导向外膜活性转运蛋白。我们的长期目标是了解大肠杆菌的细胞质和外膜之间依赖TONB依赖性能量转导的机制。 TONB中的突变使许多物种的毒性明显降低。由于铁的可用性在传染病中发挥了作用，因此广泛认为TONB系统具有潜力是开发新抗生素的新目标。额外的重要性是由于我们有助于对能量转导机制的广泛理解的能力。目前没有依赖TONB的能量转导的范式，但基于同源性，至少有三个这样的系统将PMF转导为实际上所有革兰氏阴性细菌的有用工作。除EXBB/D蛋白外，还有tolq/r蛋白（OM完整性所需）和MOTA/B蛋白（运动性需要）。因此，随着广泛的原则的出现，我们的结果还将为其他能源转导系统的基本知识做出重要贡献。按照特定的目的，我们将解决TONB系统中的三个基本问题：胞质膜上TONB能量的决定因素是什么，将能量形式转换为外膜转运蛋白，转运蛋白如何通过TONB燃烧？公共卫生相关性：几乎所有革兰氏负面细菌都使用TONB系统来规避其外膜造成的铁的局限性。了解TONB系统通过遍布外膜的传输的分子机制的理解将使未来的新抗生素开发可防止铁的摄取。病原体获得铁的能力是传染病中重要的毒力决定因素。