Structure Changes of Ion-motive ATPases

离子动力ATP酶的结构变化

• 批准号: 8187678
• 负责人: Seth L Robia
• 金额: $ 37.38万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8187678
• 关键词: ATP phosphohydrolase; Binding; Ca(2+)-Transporting ATPase; Calcium; Calcium ion; Cardiac; Cardiac Myocytes; Cell membrane; Cells; Chemicals; Contracts; Coupled; Crystallography; Data; Disease; Enzymatic Biochemistry; Enzymes; Fluorescence; Fluorescence Resonance Energy Transfer; Fluorescent Probes; Freezing; Goals; Health; Heart; Heart Diseases; Heart failure; Heterogeneity; Human; Hypertrophy; In Vitro; Individual; Ion Pumps; Ion Transport; Ions; Kinetics; Life; Ligands; Measurement; Measures; Membrane Proteins; Methods; Molecular Conformation; Motion; Myocardium; Na(+)-K(+)-Exchanging ATPase; Outcome; Pharmaceutical Preparations; Phase; Physiological; Play; Population; Positioning Attribute; Process; Protein Dynamics; Proteins; Pump; Relaxation; Research; Reticulum; Roentgen Rays; Role; Sampling; Shapes; Site; Spectrum Analysis; Structure; Structure-Activity Relationship; TAC1 gene; Techniques; Testing; Therapeutic Intervention; base; effective therapy; human disease; in vivo; insight; research study; theories

DESCRIPTION (provided by applicant): The proposed research focuses on the SERCA calcium pump and the NKA sodium pump. These are two of a class of proteins called "Ion-motive ATPases", enzymes that use the energy of ATP to pump ions across cell membranes. Ion pumps play an important role in all cells, and disordered function of these enzymes is associated with human disease, including heart failure. The proposed research will use advanced fluorescence methods to measure the structures and motions of ion pumps in living cardiac muscle cells. We will test three major hypotheses: 1) Ion pumps undergo very large structure changes. 2) These large slow changes are regulated by fast protein dynamics. 3) Regulatory partners continually bind and unbind from the pump with fast kinetics. By measuring ATPase structures and motions in live cardiac cells, we will gain new insight into mechanisms that become disrupted in failing cardiac muscle. PUBLIC HEALTH RELEVANCE: Ion pumps occupy a central position in human health, and they are key targets for therapeutic intervention in several important disease processes including heart failure. This research focuses on two ion pumps: the sodium pump (NKA) and the calcium pump (SERCA). Disordered NKA function is associated with hypertrophy and heart failure. Targeting this pump with inhibitory drugs is one of the oldest and most effective treatments for the inadequate contractility of the failing heart. SERCA is responsible for pumping calcium, the ion that coordinates the contraction and relaxation of the cardiac muscle. Optimal calcium handling is critical for normal cardiac function, and deranged SERCA activity has been implicated as a cause and an effect of heart failure. A comparison of these structurally similar pumps will yield insight into common functional mechanisms, and may reveal new opportunities to intervene in the process of heart disease.

描述（由申请人提供）：拟研究的重点是SERCA钙泵和NKA钠泵。这是一类叫做“离子驱动ATP酶”的蛋白质中的两种，这种酶利用ATP的能量将离子泵过细胞膜。离子泵在所有细胞中都起着重要作用，这些酶的功能紊乱与人类疾病有关，包括心力衰竭。提出的研究将使用先进的荧光方法来测量活心肌细胞中离子泵的结构和运动。我们将测试三个主要假设：1)离子泵经历了非常大的结构变化。2)这些大的缓慢变化是由快速的蛋白质动力学调节的。3)监管合作伙伴以快速动力学不断地与泵结合和解除结合。通过测量活心肌细胞中atp酶的结构和运动，我们将对衰竭心肌中被破坏的机制有新的认识。