Specificity and Control of Signaling by S-Nitrosation

S-亚硝化信号传导的特异性和控制

基本信息

批准号：
7778897
负责人：
MICHAEL A. MARLETTA
金额：
$ 27.59万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-01 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7778897
关键词：
Accounting Affect Affinity Apoptosis Binding Biochemical Biological Biological Assay Blood Vessels Brain Cardiovascular Diseases Caspase Cell physiology Cells Chemicals Complex Cysteine Development Disease Enzymes Event Excision Fluorescence Spectroscopy Genetic Transcription Health Care Costs Human Human Biology Hypertension Immunity In Vitro Inflammation Lead Matrix Metalloproteinases Mediating Modification Molecular Myocardial Neoplasm Metastasis Neurons Nitric Oxide Nitrosation Organ Oxides Pathway interactions Peptides Perfusion Physiological Physiological Processes Physiology Plasma Platelet aggregation Play Post-Translational Protein Processing Process Protein Isoforms Proteins Reaction Reagent Relaxation Reporting Research Role Screening procedure Sepharose Signal Transduction Signal Transduction Pathway Skin Soluble Guanylate Cyclase Specificity Spectrum Analysis Sulfhydryl Compounds Synaptic plasticity Thioredoxin Vasodilation Work Zinc Fingers base caspase-3 cyclooxygenase 2 effective therapy protein function protein protein interaction research study small molecule tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): The controls governing S-nitrosation are unknown. In addition, the ramifications of S-nitrosation signaling are virtually unknown. Determining the molecular mechanism(s) that permits cells to achieve specificity in S-nitrosation reactions is the focus of this proposal. Nitric oxide (NO) plays integral roles in mammalian physiology including vasodilation, neuronal signaling, and immunity. NO affects cellular physiology by multiple pathways. The best studied pathway is through binding to the enzyme, soluble guanylate cyclase (sGC). The actions of NO that have been described cannot be completely accounted for when only considering sGC as a target. S-Nitrosation is one type of sGC-independent signaling and involves the post-translational modification of cysteine on proteins. In many cases, modification of a cysteine alters protein function. Processes similar to this are almost exclusively a regulated cellular event with a biological machinery in tight control. In vitro work has shown that when NO reacts with a protein, many cysteine thiols are modified. However, in a cellular context when NO was not added but produced by the cell itself, multiple modifications never occur. Additionally, NO is synthesized at very low concentrations such that without a control mechanism in place, protein modification would be highly inefficient. The most logical explanation for such disparities is that the in vitro experiment lacked the cellular components that confer specificity to the S-nitrosation reaction. Experimentally, this project will attempt to identify these components by using a variety of advanced tools such as: tailored affinity probes, inductively-coupled plasma spectroscopy, fluorescence spectroscopy, and recently developed S-nitrosation specific biochemical assays. Nitric oxide (NO) mediates blood vessel relaxation, complex aspects of myocardial function, perfusion and function of all major organs, synaptic plasticity in the brain, platelet aggregation, skin function, and numerous other physiological processes. Given the role of NO in human biology, a complete understanding of the molecular details involved in its signaling will have clear application to the understanding and treatment of a broad spectrum of diseases, such as hypertension and cardiovascular disease. This research can lead to the development of more effective therapies and, potentially, reduce health care costs.

描述（由申请人提供）：控制S-硝化的控件未知。另外，S-硝化信号的后果实际上是未知的。确定允许细胞在S-硝化反应中达到特异性的分子机制是该提案的重点。一氧化氮（NO）在哺乳动物生理学中起着不可或缺的作用，包括血管舒张，神经元信号传导和免疫。没有多种途径会影响细胞生理。最好的研究途径是通过结合酶，可溶性鸟苷酸环化酶（SGC）。仅在将SGC视为目标时，就无法完全解释NO的行为。 S-硝化是一种独立于SGC的信号传导的一种类型，涉及半胱氨酸在蛋白质上的翻译后修饰。在许多情况下，半胱氨酸的修饰会改变蛋白质功能。与此类似的过程几乎完全是一个受调节的细胞事件，具有紧密控制的生物机械。体外工作表明，当没有与蛋白质反应时，许多半胱氨酸硫醇会被修饰。但是，在没有添加NO但由细胞本身产生的细胞环境中，从未发生过多次修改。此外，在非常低的浓度下合成不合理，因此如果没有控制机制，蛋白质的修饰将是高效的。这种差异的最合乎逻辑的解释是，体外实验缺乏赋予S-硝化反应特异性的细胞成分。在实验上，该项目将尝试通过使用各种高级工具（例如：量身定制的亲和力探针，电感耦合的等离子体光谱，荧光光谱法）以及最近开发的S-亚硝化特异性生化测定法。一氧化氮（NO）介导了血管松弛，心肌功能的复杂方面，所有主要器官的灌注和功能，大脑中的突触可塑性，血小板聚集，皮肤功能以及许多其他生理过程。鉴于NO在人类生物学中的作用，对其信号传导所涉及的分子细节的完全理解将在理解和治疗广泛的疾病（例如高血压和心血管疾病）中明确应用。这项研究可以导致更有效的疗法的发展，并可能降低医疗保健成本。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chemoproteomic Strategy to Quantitatively Monitor Transnitrosation Uncovers Functionally Relevant S-Nitrosation Sites on Cathepsin D and HADH2.

DOI：
10.1016/j.chembiol.2016.05.008
发表时间：
2016-06-23
期刊：
Cell chemical biology
影响因子：
8.6
作者：
Zhou Y;Wynia-Smith SL;Couvertier SM;Kalous KS;Marletta MA;Smith BC;Weerapana E
通讯作者：
Weerapana E

Mechanism and kinetics of inducible nitric oxide synthase auto-S-nitrosation and inactivation.

诱导型一氧化氮合酶自动 S-亚硝化和失活的机制和动力学。