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Antioxidant signaling by protein AMPylation

蛋白质 AMPylation 的抗氧化信号传导

基本信息

批准号：
10331027
负责人：
Vincent Scott Tagliabracci
金额：
$ 32.45万
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/10331027
关键词：
Active Sites Adopted Aging Amino Acids Antioxidants Bacteria Biology Cells Characteristics Crystallization Cyclic AMP-Dependent Protein Kinases DNA Damage 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 diagnostic tool disulfide bond glutaredoxin human disease in vivo infancy innovation inorganic phosphate mortality neglect novel novel strategies response selenol selenoprotein sensor therapeutic target 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.

项目总结