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NO signaling by a Soluble Guanylyl Cyclase -Thioredoxin transnitrosation complex

可溶性鸟苷酸环化酶-硫氧还蛋白转亚硝基复合物的 NO 信号传导

基本信息

批准号：
10680605
负责人：
ANNIE V BEUVE
金额：
$ 43.11万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10680605
关键词：
Actins Adenoviruses Affect Angiotensin II Apoptosis Binding Biochemical Bioinformatics Biological Assay Blood Vessels CRISPR/Cas technology Calcium Cardiac Cardiac Myocytes Cardiovascular system Cell Line Cell Separation Cell physiology Cells Co-Immunoprecipitations Compensation Complex Consensus Cyclic GMP Cysteine Environment Equilibrium Functional disorder Funding Guanosine Triphosphate Heart Hypertrophy Heart failure Homeostasis Hypertension Impairment Investigation Knock-in Knock-in Mouse Ligation Mass Spectrum Analysis Measures Mediator Metabolic Pathway Modeling Modification Mus Mutation Analysis Nitric Oxide Nitrosation OLFM4 gene Oxidation-Reduction Oxidative Stress Oxidative Stress Induction Pathologic Pathway interactions Peptides Physiological Polymers Post-Translational Protein Processing Property Proteins Proteomics Regulation Role SKIL gene Signal Pathway Signal Transduction Signaling Molecule Site Skeleton Smooth Muscle Soluble Guanylate Cyclase Specificity Stress Sulfhydryl Compounds System TXN gene Vasodilation Wild Type Mouse angiogenesis blood pressure regulation cGMP production cardioprotection desensitization heme a in vivo mouse model novel oxidation polymerization protective effect protective pathway protein function protein protein interaction response stress reduction

项目摘要

PROJECT SUMMARY Nitric oxide (NO) is an important signaling molecule that regulates diverse functions relevant to vascular function, apoptosis and angiogenesis. NO is best known for its ability to stimulate soluble guanylyl cyclase (now called GC1) to produce cGMP and stimulate its downstream signaling pathways. However, NO can also covalently modify cysteines (Cys) via S-nitrosation or S-nitrosylation (addition of a NO moiety to the cysteine of a protein, SNO). Although this reversible post-translational modification is increasingly recognized as an important regulatory mechanism of protein function, dynamic regulation of protein nitrosation specificity is poorly understood. Our most recent investigations reveal that GC1 has a transnitrosylase activity, i.e. GC1 has the ability to directly transfer SNO to specific targets by protein-protein interaction (transnitrosation). This transnitrosation activity does not require the cGMP forming activity of GC1 and can be accomplished by a single subunit of GC1 (formation of cGMP requires 2 subunits). Furthermore, we showed that one transnitrosation target of GC1 is oxidized thioredoxin 1 (oTrx1), a thiol-redox protein that modulates cellular S-nitrosation. In fact, oxidative/nitrosative conditions appear to favor the GC1-Trx1 complex. Using advanced proteomics approaches, we recently identified the Cys in GC1 and Trx1 that are involved in the SNO transfer in a purified system, and the Cys of proteins targeted by the GC1/Trx1 transnitrosation cascade in smooth muscle and cardiac cells. Our hypothesis is that the function of GC1 transnitrosation activity is an adaptive response to oxidative stress and potentially compensates for the dysfunction of the canonical NO-GC1-cGMP pathway that occurs in oxidative conditions. To explore this provocative hypothesis, we propose to conduct mutational analysis of the Cys we have identified to characterize the mechanism of transnitrosation in smooth muscle and cardiac cells. By comparing the targets of GC1, Trx1 and both we will determine the mechanisms underlying target specificity. We will determine how GC1/Trx1 transnitrosation of specific targets affects their cellular function. For this, we will use cell lines and primary cells isolated from a novel mouse knock-in (KI) of a Cys of GC1 involved in transnitrosation. To determine the physiological relevance of GC1- and GC1/Trx1-transnitrosation in the cardiovascular system and the adaptive response to stress, we will use the Cys KI mouse model and inhibitory peptides that disrupt the GC1/Trx1 transnitrosating complex under Angiotensin II-induced oxidative stress. This project could lead to the discovery of novel cardiovascular protective pathways driven by specific S- nitrosation.

项目总结

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inhibitory Peptide of Soluble Guanylyl Cyclase/Trx1 Interface Blunts the Dual Redox Signaling Functions of the Complex.

DOI：
10.3390/antiox12040906
发表时间：
2023-04-10
期刊：
ANTIOXIDANTS
影响因子：
7
作者：
Cui, Chuanlong;Shu, Ping;Sadeghian, Tanaz;Younis, Waqas;Li, Hong;Beuve, Annie
通讯作者：
Beuve, Annie

Proteomic cellular signatures of kinase inhibitor-induced cardiotoxicity.

DOI：
10.1038/s41597-021-01114-3
发表时间：
2022-01-20
期刊：
Scientific data
影响因子：
9.8
作者：
Xiong Y;Liu T;Chen T;Hansen J;Hu B;Chen Y;Jayaraman G;Schürer S;Vidovic D;Goldfarb J;Sobie EA;Birtwistle MR;Iyengar R;Li H;Azeloglu EU
通讯作者：
Azeloglu EU

Selective cysteines oxidation in soluble guanylyl cyclase catalytic domain is involved in NO activation.