Antioxidant signaling by protein AMPylation

蛋白质 AMPylation 的抗氧化信号传导

基本信息

批准号：
10092201
负责人：
Vincent Scott Tagliabracci
金额：
$ 32.4万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10092201
关键词：
Active Sites Adopted Aging Amino Acids Antioxidants Bacteria Biology Cells Characteristics Crystallization Cyclic AMP-Dependent Protein Kinases DNA Damage Diagnostic Disease Enzymes Escherichia coli Eukaryota Goals Health Homeostasis Homologous Gene Human Human Biology In Vitro Intervention Ketoglutarate Dehydrogenase Complex Lead Link Malignant Neoplasms Mammalian Cell Membrane Lipids Metabolism Mitochondria Mitochondrial Proteins Molecular Molecular Conformation Morbidity - disease rate Myocardial Infarction Names Nucleic Acids Oncogenic Oxidation-Reduction Oxidative Stress Oxides Oxidoreductase Pathologic Pathology Pathway interactions Patients Pattern Peripheral Vascular Diseases Pharmacology Phosphorylation Phosphotransferases Physiological Play Positioning Attribute Post-Translational Protein Processing Process Protein Kinase Proteins Public Health Reactive Oxygen Species Regulation Reperfusion Injury Role Selenium Selenocysteine Signal Pathway Signal Transduction Signaling Protein Stroke Structure Sulfhydryl Compounds Sulfur Symptoms Trees United States Work Yeasts alpha ketoglutarate analog biological adaptation to stress cell growth regulation cell injury disulfide bond glutaredoxin human disease in vivo infancy innovation inorganic phosphate mortality neglect novel novel strategies response selenol selenoprotein sensor therapeutic target tool virtual

项目摘要

Project Summary We have discovered that the predicted inactive pseudokinase selenoprotein O (SelO) adopts an atypical protein kinase fold, yet transfers AMP instead of phosphate to protein substrates in a post translational modification known as AMPylation. Our results illustrate the catalytic versatility of the protein kinase superfamily and suggest that AMPylation may be a more widespread post translational modification than previously appreciated. SelO localizes to the mitochondria, AMPylates proteins involved in cellular metabolism and redox biology, and appears to regulate an ancient and highly conserved cellular antioxidant signaling pathway. In higher eukaryotes, SelO contains the 21st genetically encoded amino acid, selenocysteine, which we propose functions as a redox sensor to regulate SelO activity in response to oxidative stress. Although reactive oxygen species are an obligatory part of human biology, elevated levels are characteristic of many disease states. For example, elevated reactive oxygen species can lead to DNA damage, which can initiate oncogenic transformation leading to cancer. Furthermore, alterations in redox homeostasis are implicated in the pathology of conditions such as stroke, heart attack, and peripheral vascular disease, all of which are major contributors to morbidity and mortality in United States. Therefore, a mechanistic understanding of the pathways that protect cells from oxidative stress could have major impacts on human health and disease. The major goal of this proposal is to determine the molecular mechanisms by which SelO-dependent AMPylation of mitochondrial proteins protects cells from oxidative stress and regulates redox homeostasis. As part of this work, we will determine the functional consequences of SelO-catalyzed AMPylation of a subset of substrates as well as the structural basis for the redox-dependent regulation of SelO activity. We anticipate that the results obtained herein will have the potential to define new paradigms of cellular regulation and redox signaling and could lead to innovative diagnostic tools or novel approaches for the treatment of human diseases.

项目摘要我们发现，预测的非活性假子酶硒蛋白O（Selo）采用了非典型蛋白激酶折叠，但在翻译后修饰中转移AMP而不是磷酸盐转移到蛋白质底物被称为两极。我们的结果说明了蛋白激酶超家族的催化多功能性两臂化可能比以前所欣赏的更广泛的翻译后修饰更广泛。塞洛定位于线粒体，对成熟的蛋白质参与细胞代谢和氧化还原生物学，并且似乎调节古老而高度保守的细胞抗氧化信号通路。在更高的真核生物中，塞洛包含第21个遗传编码的氨基酸，硒代半胱氨酸，我们提出作为氧化还原传感器的作用响应氧化应激而调节SELO活性。尽管活性氧是人类生物学的强制性部分，但升高的水平是许多疾病状态。例如，升高的活性氧可能会导致DNA损伤，这可以启动致癌转化导致癌症。此外，氧化还原稳态的改变是与中风，心脏病发作和周围血管疾病等疾病的病理有关这是美国发病率和死亡率的主要因素。因此，机械理解保护细胞免受氧化应激的途径可能会对人类健康和疾病产生重大影响。该提案的主要目的是确定依赖selo依赖性的两极的分子机制线粒体蛋白可以保护细胞免受氧化应激，并调节氧化还原稳态。作为其中的一部分工作，我们将确定selo催化的底物子集的旋转两极的功能后果作为以及依赖氧化还原活性调节的结构基础。我们预计结果此处获得的可能有可能定义细胞调节和氧化还原信号传导和可能导致创新的诊断工具或新颖的方法来治疗人类疾病。