EUKARYOTIC CHAPERONIN
真核伴侣蛋白
基本信息
- 批准号:8361063
- 负责人:
- 金额:$ 6.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-01-01 至 2011-12-31
- 项目状态:已结题
- 来源:
- 关键词:ATP HydrolysisActinsAdoptedAlzheimer&aposs DiseaseBindingBiochemicalCell divisionCellsCollaborationsComplementComplexCryoelectron MicroscopyCyclin EDiseaseElectron MicroscopyFundingGrantHydrolysisKnowledgeLightMalignant NeoplasmsMediatingMediator of activation proteinMethodsMolecularMolecular ChaperonesMolecular ConformationNational Center for Research ResourcesPrincipal InvestigatorPrion DiseasesProteinsReactionResearchResearch InfrastructureResourcesRoentgen RaysShapesSourceStagingStressStructureTubulinUnited States National Institutes of HealthVon Hippel-Lindau Tumor Suppressor Proteinanalogbasechaperonincostmacromoleculeprotein foldingprotein function
项目摘要
This subproject is one of many research subprojects utilizing the resources
provided by a Center grant funded by NIH/NCRR. Primary support for the subproject
and the subproject's principal investigator may have been provided by other sources,
including other NIH sources. The Total Cost listed for the subproject likely
represents the estimated amount of Center infrastructure utilized by the subproject,
not direct funding provided by the NCRR grant to the subproject or subproject staff.
Molecular chaperones are key mediators of cellular folding. The eukaryotic chaperonin
TRiC/CCT is essential to fold a wide array of cellular proteins. Its substrates include key
proteins essential for cell division, such as actin, tubulin, cyclin E and the tumor
suppressor protein VHL.
TRiC is a 1 MDa ring-shaped hetero-oligomeric complex that uses ATP-binding and
hydrolysis to drive the folding cycle. It is composed of 2 rings containing 8 different but
highly similar subunits in each ring. Little is known about the conformational changes that
accompany ATP-binding and hydrolysis. We have recently carried out biochemical and
biophysical studies to characterize its conformational cycle. The structural analysis by
cryoEM will provide a critical complement to the biochemical analysis.
Biomedical relevance of the study: Recent findings indicating that misfolding and
accumulation of incorrectly folded proteins is the molecular basis of many diseases,
including cancer, Alzheimer's and Prion Diseases, underscore the importance of
understanding the mechanisms of chaperone-mediated folding. Thus, knowledge of how
chaperones function to promote folding in the cell should eventually provide the basis for
controlling protein function under normal conditions, and during abnormal conditions of
environmental stress and disease.
TRiC is a ATP-dependent chaperonin with a built-in lid. Our preliminary results using
biochemical methods and Small Angle X-ray Scattering indicate changes in ATP during the
hydrolysis cycle drive the closing and opening of the lid. The collaboration with NCMI will
shed light on the conformation adopted by TRiC during the ATP hydrolysis cycle. Using
analogues of ATP that mimic distinct stages of the ATP hydrolysis reaction, we will detect
the conformational changes that drive chaperonin-mediated folding. In a separate suite of
studies, we will also investigate the structure of the TRiC-bound substrate. These studies
will be an ideal complement to our mechanistic biochemical and biophysical studies.
这个子项目是利用资源的许多研究子项目之一。
由NIH/NCRR资助的中心拨款提供。对子项目的主要支持
子项目的首席调查员可能是由其他来源提供的,
包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能
表示该子项目使用的中心基础设施的估计数量,
不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。
分子伴侣是细胞折叠的关键介体。真核细胞伴侣蛋白
TIC/CCT对于折叠一系列广泛的细胞蛋白质是必不可少的。其基材包括键
细胞分裂所必需的蛋白质,如肌动蛋白、微管蛋白、细胞周期蛋白E和肿瘤
抑制蛋白VHL。
TIC是一种1-丙二醛环状杂寡体复合体,它使用ATP结合和
水解液驱动折叠循环。它由2个环组成,其中包含8个不同的但
每个环中的亚基高度相似。人们对这种构象的变化知之甚少
伴随着ATP的结合和水解。我们最近进行了生化和
生物物理研究,以表征其构象循环。的结构分析
低温电子显微镜将为生化分析提供关键的补充。
该研究的生物医学相关性:最近的研究结果表明,错误折叠和
错误折叠的蛋白质积累是许多疾病的分子基础,
包括癌症、阿尔茨海默氏症和Prion疾病,强调了
了解伴侣蛋白介导的折叠机制。因此,了解如何
伴侣蛋白在细胞中促进折叠的功能最终应该为
在正常情况下和在非正常情况下控制蛋白质功能
环境压力和疾病。
TRIC是一种依赖于ATP的伴侣,有一个内置的盖子。我们的初步结果是使用
生化方法和小角X射线散射法表明在
水解循环驱动盖子的关闭和打开。与NCMI的合作将
阐明了TIC在ATP水解循环中采用的构象。vbl.使用
模拟ATP水解反应不同阶段的ATP类似物,我们将检测到
推动伴侣蛋白介导的折叠的构象变化。在一套单独的
在研究过程中,我们还将研究电性结合衬底的结构。这些研究
将是我们机械、生化和生物物理研究的理想补充。
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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JUDITH FRYDMAN其他文献
JUDITH FRYDMAN的其他文献
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{{ truncateString('JUDITH FRYDMAN', 18)}}的其他基金
Building a Toolbox of Sensors and Approaches to Monitor the Proteostasis Network Core B
构建监测蛋白质稳态网络核心 B 的传感器和方法工具箱
- 批准号:
10432028 - 财政年份:2018
- 资助金额:
$ 6.13万 - 项目类别:
Dissecting the aging-associated decline in cellular proteostasis - Project 1
剖析与衰老相关的细胞蛋白质稳态下降 - 项目 1
- 批准号:
10432032 - 财政年份:2018
- 资助金额:
$ 6.13万 - 项目类别:
Dissecting the aging-associated decline in cellular proteostasis - Project 1
剖析与衰老相关的细胞蛋白质稳态下降 - 项目 1
- 批准号:
10183114 - 财政年份:2018
- 资助金额:
$ 6.13万 - 项目类别:
Building a Toolbox of Sensors and Approaches to Monitor the Proteostasis Network Core B
构建监测蛋白质稳态网络核心 B 的传感器和方法工具箱
- 批准号:
10183111 - 财政年份:2018
- 资助金额:
$ 6.13万 - 项目类别:
Defining the role of Host Hsp70 Subnetworks in Dengue Virus Replication
定义主机 Hsp70 子网在登革热病毒复制中的作用
- 批准号:
9215112 - 财政年份:2016
- 资助金额:
$ 6.13万 - 项目类别:
Defining the role of Host Hsp70 Subnetworks in Dengue Virus Replication
定义主机 Hsp70 子网在登革热病毒复制中的作用
- 批准号:
10054971 - 财政年份:2016
- 资助金额:
$ 6.13万 - 项目类别:
2013 Stress Proteins in Growth, Development & Disease Gordon Research Conference
2013 生长、发育中的应激蛋白
- 批准号:
8597489 - 财政年份:2013
- 资助金额:
$ 6.13万 - 项目类别:
2011 Stress Proteins in Growth, Development and Disease GRC
2011 生长、发育和疾病 GRC 中的应激蛋白
- 批准号:
8193579 - 财政年份:2011
- 资助金额:
$ 6.13万 - 项目类别:
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