Mechanisms regulating proteasomal substrate degradation
蛋白酶体底物降解的调节机制
基本信息
- 批准号:10247747
- 负责人:
- 金额:$ 30.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-07-01 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:26S proteasomeATP phosphohydrolaseAddressAffectAnimal ModelArchaeaBindingBinding ProteinsBiochemicalBiologicalBiological ModelsBiologyCaenorhabditis elegansCatalysisCell NucleusCell physiologyCellsChargeCoiled-Coil DomainComplexDataDiseaseDisulfidesEndoplasmic Reticulum Degradation PathwayEukaryotaFoundationsGoalsHandHomologous GeneHumanImpairmentIn VitroInterferonsLifeMalignant NeoplasmsMammalsMapsMissionModelingMolecularMolecular ConformationMultiple MyelomaMutagenesisN-terminalNematodaNerve DegenerationNeurodegenerative DisordersNuclearNuclear ProteinNuclear ProteinsNucleosome Core ParticleOccupationsPeptide HydrolasesPlayPositioning AttributePost-Translational Protein ProcessingProcessPropertyProteasome InhibitionProteinsPublic HealthRecombinantsRegulationResearchRoleSiteStructureSystemTP53 geneTestingUbiquitinUnited States National Institutes of HealthYeastsbasebiochemical modelc-myc Genescrosslinkdesignfield studyhuman diseasein vitro Assayin vivointerestmulticatalytic endopeptidase complexmutantneoplasticnovelprotein degradationprotein misfoldingtherapeutic developmenttherapeutic evaluationtherapy developmenttranscription factor
项目摘要
PROJECT SUMMARY/ABSTRACT
The Ubiquitin Proteasome System (UPS) regulates the degradation of the majority of proteins in the cell and, as such, it is
involved in essentially every cellular process. Because of its central role, misregulation within the UPS can potentiate or
cause diseases, such as neurodegeneration and cancer. It is now well understood that protein misfolding and
accumulation, which are intimately associated with neurodegenerative disease, can impair the UPS, exacerbating the
disease. In fact, there is great interest to find ways of activating proteasome function as possible treatments for
neurodegenerative disorders. To the contrary, in neoplastic disease the UPS is often exploited and even upregulated; due
to this, a first line treatment for multiple myeloma is proteasome inhibition. The UPS thus sits at a shared and critical
position in these two major human diseases. The proteasome—the central degradative machinery of the UPS—is
regulated by very different regulatory complexes (e.g. 19S, PA28, PA28, PA200, and putatively P97). The job of these
complexes is to regulate the function of the core particle of the proteasome, the 20S, which isolates its protein degradation
chamber from the cellular milieu. A commonality shared by these regulators is that they all function to induce opening of
the 20S proteasome substrate gate, which exposes substrates to the interior degradation chamber. The proteasome, and
its regulators, provide a rich regulatory landscape to develop therapies that could profoundly impact these two large fields
of study. This will require a deep biochemical understanding of the involved molecular mechanisms. The recent barrage
of proteasomal structures facilitate this effort, but structures without an understanding of the dynamic mechanisms that
underlie their functions are limited. Therefore, this proposal is primarily focused on understanding the biochemical
function of three of these diverse proteasomal complexes and defining how they regulate protein degradation. We will
focus on three specific questions: 1) How do the N-terminal domains of the proteasomal ATPases affect proteasome
function?, 2) How does the mammalian P97 function to stimulate protein degradation by the 20S proteasome?, and 3)
How does PA28 regulate 20S function to catalyze nuclear protein degradation? We have chosen to focus on these three
regulators because they each play unique roles in the types of substrates that they degrade, and they each play key roles
in specific human diseases. We implement a variety of approaches and systems to address these questions including
studying function of proteasomal regulators from archaea, yeast, nematodes, mammals, and humans. Furthermore, we
are using C. elegans as an animal model system to test our biochemically derived models and genetically test therapeutic
concepts. The successful completion of this study will produce a sustained impact in the field by defining the central
mechanisms of these three different cellular strategies for regulating protein degradation, each of which play different
but critical roles in biology and disease.
项目总结/摘要
泛素蛋白酶体系统(UPS)调节细胞中大多数蛋白质的降解,因此,它是
参与了几乎所有的细胞过程。由于其核心作用,UPS内部的误调节可能会增强或
导致疾病,如神经退化和癌症。现在已经很好地理解,蛋白质错误折叠和
与神经退行性疾病密切相关的累积可以损害UPS,加剧
疾病事实上,人们对寻找激活蛋白酶体功能的方法作为可能的治疗方法非常感兴趣。
神经退行性疾病相反,在肿瘤性疾病中,UPS经常被利用,甚至上调;
对此,多发性骨髓瘤的一线治疗是蛋白酶体抑制。因此,UPS位于共享和关键的
在这两大人类疾病中的地位。蛋白酶体是UPS的中心降解机制,
由非常不同的调节复合物(例如19 S、PA 28 β、PA 28 β、PA 200和puppet P97)调节。这些人的工作
复合物的作用是调节蛋白酶体的核心颗粒20 S的功能,20 S分离其蛋白质降解
从细胞环境中分离出来。这些调节器共有的一个共同点是,它们都起到诱导开放的作用。
20 S蛋白酶体底物门,将底物暴露于内部降解室。蛋白酶体,
其监管机构提供了丰富的监管环境,以开发可能对这两大领域产生深远影响的疗法
学习。这将需要对所涉及的分子机制有深入的生物化学理解。最近的弹幕
对蛋白酶体结构的了解有助于这一努力,但对蛋白酶体结构的动力学机制缺乏了解,
其功能是有限的。因此,这项建议主要集中在了解生物化学
这些不同的蛋白酶体复合物的功能,并确定它们如何调节蛋白质降解。我们将
本文主要讨论三个问题:1)蛋白酶体ATP酶N端结构域对蛋白酶体的影响
功能?2)哺乳动物P97如何通过20 S蛋白酶体刺激蛋白质降解?,和3)
PA 28 β如何调节20 S功能以催化核蛋白降解?我们选择重点关注这三个方面
因为它们各自在降解的底物类型中扮演着独特的角色,
具体的人类疾病。我们实施了各种方法和系统来解决这些问题,包括
研究来自古细菌、酵母、线虫、哺乳动物和人类的蛋白酶体调节剂的功能。而且我们
使用C。elegans作为动物模型系统来测试我们的生化衍生模型和基因测试治疗
理念的这项研究的成功完成将通过确定核心的
这三种不同的调节蛋白质降解的细胞策略的机制,每一种都发挥不同的作用,
但在生物学和疾病中起着关键作用。
项目成果
期刊论文数量(0)
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{{ truncateString('David Matthew Smith', 18)}}的其他基金
Mechanisms regulating proteasomal substrate degradation
蛋白酶体底物降解的调节机制
- 批准号:
8694173 - 财政年份:2014
- 资助金额:
$ 30.4万 - 项目类别:
Mechanisms regulating proteasomal substrate degradation
蛋白酶体底物降解的调节机制
- 批准号:
9301593 - 财政年份:2014
- 资助金额:
$ 30.4万 - 项目类别:
Mechanisms regulating proteasomal substrate degradation
蛋白酶体底物降解的调节机制
- 批准号:
10474492 - 财政年份:2014
- 资助金额:
$ 30.4万 - 项目类别:
Mechanisms regulating proteasomal substrate degradation
蛋白酶体底物降解的调节机制
- 批准号:
8875711 - 财政年份:2014
- 资助金额:
$ 30.4万 - 项目类别:
Mechanisms regulating proteasomal substrate degradation
蛋白酶体底物降解的调节机制
- 批准号:
10022500 - 财政年份:2014
- 资助金额:
$ 30.4万 - 项目类别: