Probing the role of cysteine sulfenylation in cell signaling
探讨半胱氨酸磺酰化在细胞信号传导中的作用
基本信息
- 批准号:9380891
- 负责人:
- 金额:$ 41.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-08-01 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:Active SitesBackBiochemicalBiochemistryBiologicalBiological AssayBiological MarkersBiological ProcessBiologyBrainCellsChemicalsChemistryClustered Regularly Interspaced Short Palindromic RepeatsCodeCollaborationsComplementCultured CellsCysteineData SetDependencyDetectionDevelopmentDiseaseDrug TargetingElementsEnsureEnzymesEpidermal Growth Factor ReceptorEvaluationEventFamilyFundingGenesGenetic TranscriptionHeartHydrogen PeroxideIndividualIsotopesKnock-outKnockout MiceLearningLiverLungMalignant NeoplasmsMammalian CellMapsMediatingMedicineMetabolic DiseasesMethodsModificationMolecularMonitorMusNADPH OxidaseNeurodegenerative DisordersOrganOxidantsOxidation-ReductionOxidoreductasePathway AnalysisPathway interactionsPeptidesPhosphorylationPhosphotransferasesPhysiologicalPost-Translational Protein ProcessingPreparationProcessPropertyProtein IsoformsProtein SProtein Tyrosine KinaseProteinsProteomeProteomicsReactionRegulationReportingRepressionResearchResourcesRoleSignal PathwaySignal TransductionSiteSite-Directed MutagenesisSpecificitySulfenic AcidsSulfhydryl CompoundsSulfinic AcidsSystemTestingTherapeutic InterventionTimeTransgenic MiceVitronectinWorkadductanalytical toolbiophysical propertiesbody systemchemoproteomicscomputerized toolscysteine sulfinic acidcysteinesulfenic aciddesigndiazeneexpectationexperimental studyimprovedin vivoinsightnoveloxidationprotein structurereaction ratescaffoldstoichiometrytherapeutic targettool
项目摘要
ABSTRACT
Hydrogen peroxide (H2O2) is a versatile oxidant that mediates numerous biological functions within every major
organ system. An emerging molecular pathway by which H2O2 accomplishes functional diversity is through the
specific modification of protein cysteine residues to form S-sulfenylcysteine. This post-translational
modification, S-sulfenylation, regulates protein activity and localization. Despite considerable advances with
individual proteins, the biological chemistry, the dependency on specific H2O2-generating NADPH oxidases
(Nox), and the structural elements that govern the modification of specific cysteine residues in vivo are vastly
unknown. To provide insights into these fundamental biological questions, sensitive, validated, and quantitative
chemical proteomic approaches are needed, but remain at an early stage of development. To this end, during
the last funding period we developed and implemented a novel chemical proteomic approach. This new
method has achieved specific, efficient, complementary and selective identification of S-sulfenylated cysteine
residues in living cells. Currently, implementation of our chemoproteomic method has precisely pinpointed the
site of S-sulfenylation in 1,105 peptides on 778 proteins in cultured mammalian cells. These proteins constitute
the largest dataset of S-sulfenylated proteins reported to date. In this renewal application, we propose to use
and expand our state-of-art chemical proteomic platform towards the three major objectives of: (1) defining the
molecular determinants that govern the selection of specific cysteine resides and proteins for S-sulfenylation,
(2) elucidating the functional networks and signaling pathways that are influenced by S-sulfenylation, and (3)
identifying the enzyme system(s) that control protein desulfenylation. By uncovering the endogenous S-
sulfenylome proteomics of mouse liver, brain, lung, and heart and applying multiple analytical and
computational tools, the biochemical and structural properties that govern the specificity of S-sulfenylation in
vivo will be defined. Biological functional and pathway analyses, in conjunction with quantitative stoichiometric
assessment of S-sulfenylomes derived from Nox knockout and transgenic mice, will test H2O2-specific
functional regulation in signaling cascades within and across the four different organs. Simultaneous
acquisition of the endogenous site-specific, reactive cysteinome and phosphoproteome will enable
comprehensive and global evaluation of complementation and coordination. Enzyme system(s) that regulate
desulfenylation will be identified using CRISPR sequence-specific repression or activation of likely candidates.
Overall, the comprehensive large-scale study of protein structures and functional pathways will significantly
improve our appreciation of S-sulfenylation in H2O2-mediated biology. The molecular components of these
pathways may, in turn, represent new biomarkers and drug targets in the rapidly growing fields of ‘redox
biology and medicine’. The research tools and methods advanced in this proposal should also provide of
general value for characterizing redox networks in a range of physiological and disease processes.
摘要
过氧化氢(H2 O2)是一种多功能氧化剂,在每个主要的细胞内介导许多生物功能。
器官系统H2 O2实现功能多样性的新兴分子途径是通过
特异性修饰蛋白质半胱氨酸残基以形成S-亚磺酰基半胱氨酸。这种翻译后
修饰,S-亚磺酰化,调节蛋白质活性和定位。尽管取得了相当大的进展,
单个蛋白质,生物化学,对特定H2 O2生成NADPH氧化酶的依赖性
(Nox),并且在体内控制特定半胱氨酸残基的修饰的结构元件在很大程度上是
未知为了深入了解这些基本的生物学问题,敏感,验证和定量
化学蛋白质组学方法是必要的,但仍处于早期发展阶段。为此,在
在上一个资助期间,我们开发并实施了一种新的化学蛋白质组学方法。这个新
方法实现了S-亚磺酰半胱氨酸的特异性、高效性、互补性和选择性鉴定
活细胞中的残留物。目前,我们的化学蛋白质组学方法的实施已经精确地定位了
在培养的哺乳动物细胞中778种蛋白质上的1,105种肽中的S-亚磺酰化位点。这些蛋白质组成
迄今为止报道的S-亚磺酰化蛋白质的最大数据集。在此更新申请中,我们建议使用
并将我们最先进的化学蛋白质组学平台扩展到三个主要目标:(1)定义
控制选择特定半胱氨酸残基和蛋白质用于S-亚磺酰化的分子决定簇,
(2)阐明受S-亚磺酰化影响的功能网络和信号通路,以及(3)
鉴定控制蛋白质间苯酰化的酶系统。通过揭示内源性S-
小鼠肝、脑、肺和心脏的亚磺酰组蛋白质组学,并应用多种分析和
计算工具,生物化学和结构特性,支配特异性的S-亚磺酰化,
将定义vivo。生物功能和途径分析,结合定量化学计量
来自Nox敲除和转基因小鼠的S-亚磺酰基组的评估,将测试H2 O2特异性
在四个不同器官内和跨四个不同器官的信号级联中的功能调节。同时
获得内源性位点特异性、反应性半胱氨酸组和磷酸化蛋白质组将使
对互补性和协调性进行全面和全局性评价。调节的酶系统
将使用CRISPR序列特异性抑制或激活可能的候选物来鉴定脱亚苯基化。
总的来说,对蛋白质结构和功能通路的全面大规模研究将显著地
提高了我们对H2 O2介导生物学中S-亚磺酰化的认识。其中的分子成分
反过来,在快速发展的“氧化还原”领域,
生物学和医学”。本提案中提出的研究工具和方法还应提供
在一系列生理和疾病过程中表征氧化还原网络的一般价值。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Kate Suzanne Carroll其他文献
Kate Suzanne Carroll的其他文献
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{{ truncateString('Kate Suzanne Carroll', 18)}}的其他基金
Redox Modification and Targeting of Mutant KRas in Cancer
癌症中突变 KRa 的氧化还原修饰和靶向
- 批准号:
10595875 - 财政年份:2018
- 资助金额:
$ 41.1万 - 项目类别:
Redox Modification and Targeting of Mutant KRas in Cancer
癌症中突变 KRa 的氧化还原修饰和靶向
- 批准号:
10162539 - 财政年份:2018
- 资助金额:
$ 41.1万 - 项目类别:
Redox Modification and Targeting of Mutant KRas in Cancer
癌症中突变 KRa 的氧化还原修饰和靶向
- 批准号:
9912729 - 财政年份:2018
- 资助金额:
$ 41.1万 - 项目类别:
Nucleophilic Inhibitors for Targeting Redox-Sensitive Kinases
用于靶向氧化还原敏感激酶的亲核抑制剂
- 批准号:
9187426 - 财政年份:2013
- 资助金额:
$ 41.1万 - 项目类别:
Nucleophilic Inhibitors for Targeting Redox-Sensitive Kinases
用于靶向氧化还原敏感激酶的亲核抑制剂
- 批准号:
8969670 - 财政年份:2013
- 资助金额:
$ 41.1万 - 项目类别:
Nucleophilic Inhibitors for Targeting Redox-Sensitive Kinases
用于靶向氧化还原敏感激酶的亲核抑制剂
- 批准号:
8776280 - 财政年份:2013
- 资助金额:
$ 41.1万 - 项目类别:
Nucleophilic Inhibitors for Targeting Redox-Sensitive Kinases
用于靶向氧化还原敏感激酶的亲核抑制剂
- 批准号:
8631369 - 财政年份:2013
- 资助金额:
$ 41.1万 - 项目类别:
Probing the role of cysteine sulfenylation in cell signaling
探讨半胱氨酸磺酰化在细胞信号传导中的作用
- 批准号:
8342423 - 财政年份:2012
- 资助金额:
$ 41.1万 - 项目类别:
Probing the role of cysteine sulfenylation in cell signaling
探讨半胱氨酸磺酰化在细胞信号传导中的作用
- 批准号:
8653970 - 财政年份:2012
- 资助金额:
$ 41.1万 - 项目类别:
Chemical Tools for Probing Cysteine Sulfenation and Sulfination Redox Biology
用于探测半胱氨酸磺化和磺化氧化还原生物学的化学工具
- 批准号:
10658440 - 财政年份:2012
- 资助金额:
$ 41.1万 - 项目类别:
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