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Thiol/Disulfide Redox Regulation of Heme Oxygenase-2

血红素加氧酶 2 的硫醇/二硫化物氧化还原调节

基本信息

批准号：
8097426
负责人：
Stephen Wiley Ragsdale
金额：
$ 55.81万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8097426
关键词：
Address Affect Affinity Azides Bacteria Biliverdin reductase Biliverdine Binding Binding Sites Biogenesis Blood C-terminal Calorimetry Carotid Body Catabolism Catalytic Domain Cell Respiration Cells Cysteine Cytoplasmic Structures Cytoplasmic Tail Disulfides Drug or chemical Tissue Distribution Electrophysiology (science)Embryo Environmental air flow Enzymes Exhibits Figs - dietary Fluorescence Gap Junctions Genetic Hand Heme Heme Iron Homeostasis Human Hypoxia Immunoprecipitation In Vitro Ion Channel Iron Kinetics Length Ligands Link Lipid Peroxidation Location Mammals Measurement Measures Membrane Metabolism Metals Methods NADPH-Ferrihemoprotein Reductase Neurons Organ Organism Oxidation-Reduction Oxygen Oxygenases Physiological Play Positioning Attribute Potassium Channel Process Property Protein Biosynthesis Protein Isoforms Proteins Regulation Research Respiration Respiratory System Reticulocytes Roentgen Rays Role Signal Transduction Source Structure Sulfhydryl Compounds System Testis Brain Titrations Variant Work adduct catalyst cell growth regulation circular magnetic dichroism cysteinylproline design electronic structure experience heme a heme oxygenase-1 heme oxygenase-2 in vivo insight iron metabolism kidney cell large-conductance calcium-activated potassium channels link protein oxidative damage public health relevance research study response vector

项目摘要

DESCRIPTION (provided by applicant): Heme oxygenase (HO) catalyzes the conversion of heme to biliverdin, CO, and iron. The two isoforms, HO1 and HO2, share similar physical and kinetic properties but exhibit different physiological roles and organ locations. The structures of the core catalytic domains of HO1 and HO2 are nearly superimposable and the major distinction between these HO isoforms is the occurrence of heme regulatory motifs (HRMs) in HO2 that are lacking in HO1. The HRMs play a regulatory role as a thiol/disulfide redox switch that we have shown to regulate interactions of HO2 with substrate (heme) and with a Ca++- activated high conductance potassium channel (the BK or Slopoke channel). Regulation of K+ flux across the membrane by the BK channel enables the O2 sensing function of the carotid body, which controls respiratory system ventilation in response to changes in the blood oxygen concentration. We recently demonstrated that the BK channel also contains a thiol/disulfide redox switch that regulates binding of heme, which has been shown to control its K+ channel activity. We plan to use spectroscopic, kinetic, genetic, crystallographic, NMR, and electrophysiology methods to determine how these thiol/disulfide redox switches (the HRMs in human HO2 and the CXXC motif in the human BK channel) affect the structure and function of and interactions between these functionally linked proteins. We will determine the redox states of the heme and HRMs in vitro and in vivo under various physiological conditions. We also will perform spectroscopic and electrophysiology measurements to determine the mechanism by which HO2 influences BK channel function. PUBLIC HEALTH RELEVANCE: Heme oxygenase (HO) is the only mammalian protein known to degrade heme and sits at the nexus of several major redox and metal regulatory systems. Unlike HO1, HO2 contains two Heme Regulatory Motifs (HRMs) that form a thiol/disulfide redox switch, which regulates binding of its substrate, heme. We propose to determine how thiol/disulfide redox switches on HO2 and on a functionally related interacting partner, a heme-regulated potassium channel, regulate their structures and functions.

描述（由申请人提供）：血红素加氧酶（HO）催化血红素转化为胆绿素、CO和铁。这两种异构体HO 1和HO 2具有相似的物理和动力学特性，但表现出不同的生理作用和器官定位。HO 1和HO 2的核心催化结构域的结构几乎是重叠的，这些HO亚型之间的主要区别是HO 2中缺乏HO 1的血红素调节基序（HRM）的发生。HRM作为硫醇/二硫化物氧化还原开关发挥调节作用，我们已经证明其调节HO 2与底物（血红素）和与Ca++激活的高电导钾通道（BK或Slopoke通道）的相互作用。BK通道对跨膜K+通量的调节使颈动脉体的O2传感功能成为可能，该功能响应于血氧浓度的变化来控制呼吸系统通气。我们最近证明，BK通道还包含一个巯基/二硫化物氧化还原开关，调节血红素的结合，这已被证明可以控制其K+通道活性。我们计划使用光谱学，动力学，遗传学，晶体学，NMR和电生理学方法来确定这些硫醇/二硫化物氧化还原开关（人类HO 2中的HRM和人类BK通道中的CXXC基序）如何影响这些功能相关蛋白质的结构和功能以及它们之间的相互作用。我们将在各种生理条件下，在体外和体内测定血红素和HRM的氧化还原状态。我们还将进行光谱和电生理学测量，以确定HO 2影响BK通道功能的机制。公共卫生关系：血红素加氧酶（HO）是唯一已知的哺乳动物蛋白质降解血红素，并坐在几个主要的氧化还原和金属调节系统的连接。与HO 1不同，HO 2含有两个血红素调节基序（HRM），形成硫醇/二硫化物氧化还原开关，调节其底物血红素的结合。我们建议确定如何巯基/二硫化物氧化还原开关HO 2和功能相关的相互作用的合作伙伴，血红素调节钾通道，调节它们的结构和功能。