Serine/Threonine Phosphatases in Neurological Diseases
神经系统疾病中的丝氨酸/苏氨酸磷酸酶
基本信息
- 批准号:10583671
- 负责人:
- 金额:$ 53.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-01 至 2027-12-31
- 项目状态:未结题
- 来源:
- 关键词:A kinase anchoring proteinActive SitesAffinity ChromatographyAlzheimer&aposs DiseaseBindingBiochemicalBiologicalBiological ProcessBrainCalcineurinCell LineCellsCellular biologyCollaborationsComplexCoupledCyclic AMP-Dependent Protein KinasesCyclosporineDataDevelopmentDiseaseEnvironmentFK506FoundationsFundingImmunosuppressive AgentsKnowledgeLeadLong-Term DepressionLong-Term PotentiationMAP3K7 geneMAP3K7IP1 geneMass Spectrum AnalysisMediatingMemoryMolecularMolecular TargetNervous System PhysiologyNeuronsPPP3CA genePhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPhysiologicalPhysiologyPopulationPost-Translational Protein ProcessingProcessProtein DephosphorylationProtein phosphataseProteinsProteomeRecording of previous eventsRegulationResearchResearch PersonnelResolutionRoleScaffolding ProteinSerineShapesSignal PathwaySignal TransductionStimulusStrokeStructureSubstrate InteractionSystemTechniquesThreonineWorkcalcineurin phosphatasecell typeexperimental studyhuman diseaseinhibitorinnovationinsightnervous system disorderneuron developmentneurotransmissionnovelpalmitoylationreceptorrecruitresponsesuccesstherapeutic targettoolvoltage
项目摘要
ABSTRACT. Phosphorylation is one of the most ubiquitous, reversible posttranslational modifications in cells,
and is a critical component of most signaling cascades. Strict temporal and spatial control are essential for the
fidelity of this process, as derailed signaling cascades lead to disease. Here, we continue our long-standing
effort to investigate signaling in neurons. If neuronal signaling goes awry, the most prominent results are well
known diseases, such as Alzheimer's disease and stroke. Recently, we successfully determined how the most
ubiquitous neuronal ser/thr protein phosphatase (PPP) calcineurin (CN) recruits its substrates. Namely, CN
binds regulators and substrates via CN-specific recruitment motifs (PxIxIT and LxVP). Further, we also
discovered that CN uses an active site recognition sequence (TxxP) to target substrate phosphosites, which,
in turn, drives vital biological functions. This is the first defined active site recognition sequence for any PPP,
transforming our ability to identify novel CN-specific phosphosites. Here, we will leverage our newly established
tools and discoveries to achieve three aims. First, we will establish the CN interactome and substratome in
distinct neuronal populations. This will enable us to demonstrate the diversity of CN functions in neurons, define
if they differ in response to stimuli as well as identify the molecular substrates that are necessary for these
changes to occur. Building further on the success of the previous funding period, we will also advance our
molecular understanding of CN substrate recruitment by studying two critical CN substrate signaling platforms:
CN-AKAP5 and CN-TAK1. Specifically, we will show that the these signaling platforms utilize multiple,
competing PxIxIT/LxVP motifs to recruit CN via different proteins and show how these distinct mechanisms
define CN substrate dephosphorylation efficacy. Critically, our preliminary data suggest that posttranslational
modification of AKAP5 modulates CN control of PKA activity and ultimately receptor regulation. Finally, we
have also recently confirmed our prediction that the transforming growth factor-β activated kinase 1 (TAK1)
binds directly to CN. However, unexpectedly the TAK1 regulator TAB2 also binds directly to CN via different
LxVP and PxIxIT motifs. We will investigate the mechanisms and consequences of this interaction on CN
recruitment and TAK1 function. The modes of action and regulation of CN in the AKAP5 and TAK1 signaling
platforms are unexpected and highlight the broad variety of mechanisms used to regulate CN activity. Taken
together, the proposed studies leverage a powerful integrated approach that combines atomic resolution
techniques with biochemical and cell biology experiments to obtain novel insights into the molecular
mechanisms used to direct CN activity. Because CN has critical roles in human diseases generally, and in the
brain specifically, and because CN is the only successfully therapeutically targeted PPP (CN is the target of
the blockbuster immunosuppressants cyclosporin A and FK-506), our proposed work will provide a critically
needed molecular and cellular understanding of CN activity and regulation in neuronal function.
摘要。磷酸化是细胞中最普遍、可逆的翻译后修饰之一,
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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Wolfgang Peti其他文献
Wolfgang Peti的其他文献
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{{ truncateString('Wolfgang Peti', 18)}}的其他基金
Shared Tundra screening cryo-EM for New England
新英格兰共享 Tundra 冷冻电镜筛查
- 批准号:
10413473 - 财政年份:2022
- 资助金额:
$ 53.63万 - 项目类别:
Mechanism and activity of beta-lactam resistant enzymes in E. faecium and E. faecalis
屎肠球菌和粪肠球菌中β-内酰胺抗性酶的机制和活性
- 批准号:
10624757 - 财政年份:2019
- 资助金额:
$ 53.63万 - 项目类别:
Protein Phosphatase 1 Holoenzyme Formation and Subunit Exchange
蛋白磷酸酶 1 全酶形成和亚基交换
- 批准号:
9985412 - 财政年份:2019
- 资助金额:
$ 53.63万 - 项目类别:
Mechanism and activity of beta-lactam resistant enzymes in E. faecium and E. faecalis
屎肠球菌和粪肠球菌中β-内酰胺抗性酶的机制和活性
- 批准号:
10391315 - 财政年份:2019
- 资助金额:
$ 53.63万 - 项目类别:
Mechanism and activity of beta-lactam resistant enzymes in E. faecium and E. faecalis
屎肠球菌和粪肠球菌β-内酰胺抗性酶的机制和活性
- 批准号:
9927573 - 财政年份:2019
- 资助金额:
$ 53.63万 - 项目类别:
Dynamics & energetics of p38a kinase regulation by ligands
动力学
- 批准号:
8608555 - 财政年份:2013
- 资助金额:
$ 53.63万 - 项目类别:
Dynamics & energetics of p38a kinase regulation by ligands
动力学
- 批准号:
8436569 - 财政年份:2013
- 资助金额:
$ 53.63万 - 项目类别:
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