Structure and regulation of the ATP synthase

ATP合酶的结构和调节

• 批准号: 6693419
• 负责人: David Michael Mueller
• 金额: $ 27.73万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6693419
• 关键词: Saccharomyces cerevisiae; X ray crystallography; adenosinetriphosphatase; enzyme inhibitors; enzyme mechanism; fungal genetics; fungal proteins; gene mutation; hydrogen transporting ATP synthase; mitochondria; oxidative phosphorylation; protein structure function

DESCRIPTION (provided by applicant): The long-term goal of this project is to gain an understanding on the structure/function relationship of the ATP synthase as it relates to mechanism of the ATP synthase. This is particularly important in cardiac tissue since the ATP synthase accounts for majority of ATP made under aerobic conditions. Furthermore, regulation of the ATP synthase in heart has been shown to occur under ischemic conditions. Recently, in a collaborative study, we were able to obtain a 3.0-3.3 A electron density map of the yeast F1 ATPase. This major advance now allows us to ask and answer questions using the full tools of yeast genetics and x-ray crystallography. The studies in this proposal, in part, investigate the molecular impact of mutations in genes encoding subunits of the mitochondrial ATP synthase on the structure and function of the ATP synthase. The first aim of this study tests a hypothesis that assembly of ATP synthase can occur in the absence of key subunits and the resulting complex is responsible of the uncoupling of the mitochondria. The second aim tests the hypothesis for the mechanism of a class of mutations, mgi, isolated in subunits of the ATP synthase. The third aim will utilize x-ray crystallography to obtain a high-resolution structure of the F1-ATPase containing the mgi mutations. The fourth and final aim will test the hypothesis that the natural inhibitor of the ATP synthase prevents the unidirectional rotation of the gamma-subunit. These experiments will provide a further understanding on the structure and function of the ATP synthase, but will also provide important information on the functional consequences of mutations in subunits of the ATP synthase. Ultimately, this project will provide critical information on the regulation of the ATP synthase and the importance of this regulation on the overall capabilities of the cell to provide enough energy as demanded by tissue and organism in both the normal and disease states.

项目描述（由申请人提供）：本项目的长期目标是了解ATP合酶的结构/功能关系，因为它与ATP合酶的机制有关。这在心脏组织中特别重要，因为ATP合酶占有氧条件下产生的ATP的大部分。此外，心脏中ATP合酶的调节已显示在缺血条件下发生。最近，在一项合作研究中，我们能够获得酵母F1 ATP酶的3.0-3.3 A电子密度图。这一重大进展现在允许我们使用酵母遗传学和X射线晶体学的全部工具来提问和回答问题。在这项研究中，部分研究了线粒体ATP合酶亚基编码基因突变对ATP合酶结构和功能的分子影响。本研究的第一个目的是检验一个假设，即ATP合酶的组装可以在没有关键亚基的情况下发生，并且所产生的复合物负责线粒体的解偶联。第二个目的是测试一类突变的机制的假设，MGI，分离在ATP合酶的亚基。第三个目标将利用X射线晶体学获得含有mgi突变的F1-ATP酶的高分辨率结构。第四个也是最后一个目的是检验ATP合酶的天然抑制剂阻止γ亚基单向旋转的假设。这些实验将提供对ATP合酶的结构和功能的进一步理解，但也将提供关于ATP合酶亚基突变的功能后果的重要信息。最终，该项目将提供有关ATP合酶调节的关键信息，以及这种调节对细胞整体能力的重要性，以提供正常和疾病状态下组织和生物体所需的足够能量。