Structural and Molecular Mechanisms for Dysregulation of Protein Kinase C Gamma in Cerebellar Ataxia
小脑性共济失调中蛋白激酶 C γ 失调的结构和分子机制
基本信息
- 批准号:10394960
- 负责人:
- 金额:$ 65.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAtaxiaAutomobile DrivingBiochemicalBrainCerebellar AtaxiaCerebellar DiseasesCerebellumCryoelectron MicroscopyCyclic AMP-Dependent Protein KinasesDiglyceridesDiseaseEnzymesFluorescence Resonance Energy TransferFutureGerm-Line MutationGoalsHomeostasisIsoenzymesKnowledgeLengthMalignant NeoplasmsMolecularMolecular ConformationMotorMutationNeurodegenerative DisordersNeuronsOutputPathologyPathway interactionsPatientsPhosphotransferasesProtein RegionProteinsPublic HealthPurkinje CellsQuality ControlRegulationResearchResolutionShunt DeviceSignal PathwaySignal TransductionSignaling ProteinSpinocerebellar AtaxiasSpinocerebellar DegenerationsStructureTherapeuticVisiondisease phenotypelive cell imagingmouse modelmutantnovelphosphoproteomicsprotein functionprotein kinase C gammasensorspatiotemporalstructural biologytranscriptometranscriptome sequencing
项目摘要
Summary/Abstract
The overall vision of our proposed research is to understand the structural, molecular, and cellular
mechanisms by which germline mutations in protein kinase C gamma (PKCg) drive the neuro-
degenerative disease Spinocerebellar Ataxia 14 (SCA14). PKCg is a Ca2+/diacylglycerol-regulated kinase
expressed only in neurons, including Purkinje cells whose degeneration is a hallmark of the almost 50
subtypes of SCA. We have assembled a team with extensive and complementary expertise in structural
biology of kinases and in PKC mechanisms to understand how these mutations alter the structure and
function of PKCg to contribute to the disease phenotype. The hypothesis driving this proposal is that
mutations are concentrated at specific regions of PKCg that break autoinhibitory contacts to enhance its
activity by a novel mechanism that evades normal quality control degradation. This evasion of
degradation may be a unique feature of the Ataxia mutations as cancer-associated mutations that break
autoinhibitory contacts destabilize PKC and shunt it to degradation. Such evasion of normal quality
control allows aberrantly active PKCg to enhance its signaling output, which in Purkinje cells in the
cerebellum leads to degeneration. Furthermore, we hypothesize that enhanced signaling by PKCg may
underlie the pathology of SCA, in general, as a large fraction of SCAs are caused by mutations in proteins
that control Ca2+ homeostasis or signaling. We aim to combine computational, structural, biochemical,
live-cell imaging, and phosphoproteomics approaches to understand the molecular details of how
disease-associated mutations in PKCg impact function, with the long-term future goal of using this
knowledge to treat this devastating disease.
摘要/摘要
我们提议的研究的总体愿景是理解结构、分子和细胞
蛋白激酶C-γ(PKCG)胚系突变驱动神经细胞凋亡的机制
退行性脊髓小脑性共济失调14(SCA14)。PKCG是一种钙离子/甘油二酯调节的激酶
仅在神经元中表达,包括浦肯野细胞,其退化是近50个
SCA亚型。我们已经组建了一支拥有广泛和互补的结构专业知识的团队
了解这些突变是如何改变结构和蛋白激酶C机制的
PKCG在疾病表型中的作用。这一提议背后的假设是
突变集中在PKCG的特定区域,这些区域打破自抑制接触以增强其
通过一种新的机制,避免了正常的质量控制降级。这种逃避
降解可能是共济失调突变的一个独特特征,因为与癌症相关的突变
自身抑制接触会破坏PKC的稳定性,并将其分流到降解。这种对正常品质的回避
控制允许异常活跃的PKCG增强其信号输出,这在浦肯野细胞中
小脑会导致变性。此外,我们假设PKCG增强的信号转导可能
通常,SCA的病理基础是很大一部分SCA是由蛋白质突变引起的
控制钙离子动态平衡或信号的物质。我们的目标是将计算、结构、生化、
活细胞成像和磷蛋白组学方法来了解分子细节如何
PKCG影响功能的疾病相关突变,未来的长期目标是利用这一点
治疗这种毁灭性疾病的知识。
项目成果
期刊论文数量(0)
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ALEXANDRA C. NEWTON其他文献
ALEXANDRA C. NEWTON的其他文献
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{{ truncateString('ALEXANDRA C. NEWTON', 18)}}的其他基金
Structural and Molecular Mechanisms for Dysregulation of Protein Kinase C Gamma in Cerebellar Ataxia
小脑性共济失调中蛋白激酶 C γ 失调的结构和分子机制
- 批准号:
10605182 - 财政年份:2021
- 资助金额:
$ 65.3万 - 项目类别:
Establishing Function of Understudied PRKCQ Kinase in Cellular Regulation and Disease
建立正在研究的 PRKCQ 激酶在细胞调节和疾病中的功能
- 批准号:
9813191 - 财政年份:2019
- 资助金额:
$ 65.3万 - 项目类别:
Signal Termination by PHLPP, PH domain Leucine-rich repeat Protein Phosphatase
通过 PHLPP、PH 结构域富含亮氨酸的重复蛋白磷酸酶终止信号
- 批准号:
7892059 - 财政年份:2009
- 资助金额:
$ 65.3万 - 项目类别:
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