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：
10474492
负责人：
David Matthew Smith
金额：
$ 30.4万
依托单位：
WEST VIRGINIA UNIVERSITY
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：
https://reporter.nih.gov/project-details/10474492
关键词：
26S proteasome ATP phosphohydrolase Address Affect Animal Model Archaea Binding Binding Proteins Biochemical Biological Biological Models Biology Caenorhabditis elegans Catalysis Cell Nucleus Cell physiology Cells Charge Coiled-Coil Domain Complex Data Disease Disulfides Endoplasmic Reticulum Degradation Pathway Eukaryota Foundations Goals Hand Homologous Gene Human Impairment In Vitro Interferons Life Malignant Neoplasms Mammals Maps Mission Modeling Molecular Molecular Conformation Multiple Myeloma Mutagenesis N-terminal Nematoda Nerve Degeneration Neurodegenerative Disorders Nuclear Nuclear Protein Nuclear Proteins Nucleosome Core Particle Occupations Peptide Hydrolases Play Positioning Attribute Post-Translational Protein Processing Process Property Proteasome Inhibition Proteins Public Health Recombinants Regulation Research Role Site Structure System TP53 gene Testing Ubiquitin United States National Institutes of Health Yeasts base biochemical model c-myc Genes crosslink design field study human disease in vitro Assay in vivo interest multicatalytic endopeptidase complex mutant neoplastic novel protein degradation protein misfolding therapeutic development therapeutic evaluation therapy development transcription 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.

项目摘要/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，因此是本质上参与了每个细胞过程。由于其核心作用，UPS内部的不利位置可能会潜在或导致疾病，例如神经变性和癌症。现在众所周知，蛋白质的折叠率有些错误和与神经退行性疾病密切相关的积累可能会损害UPS，加剧该疾病疾病。实际上，有很大的兴趣找到激活蛋白酶体功能作为可能治疗的方法神经退行性疾病。与之形成鲜明对比的是，在肿瘤疾病中，UPS经常被利用甚至更新。到期的为此，多发性骨髓瘤的第一线治疗是蛋白酶体抑制。因此，UPS是一个共同且关键的在这两种主要人类疾病中的位置。蛋白酶体是UPS的中心降解机械 - 是由非常不同的调节复合物（例如19S，PA28，PA28，PA200和推定的P97）调节。这些工作复合物是调节蛋白质组的核心粒子的功能，即20s，该功能分离出蛋白质降解来自蜂窝环境的腔室。这些监管机构共有的一个共同点是，它们都起作用以诱导开放 20S蛋白酶体底物栅极，该门将底物暴露于内部降解室。蛋白酶体和它的监管机构提供了丰富的监管景观，以开发可深刻影响这两个大领域的疗法研究。这将需要对所涉及的分子机制有深刻的生化理解。最近的弹幕蛋白酶体结构准备了这一努力，但是结构不了解动态机制他们的功能是有限的。因此，该建议主要集中于理解生化这些潜水员蛋白质体复合物中的三个功能，并定义它们如何调节蛋白质降解。我们将关注三个特定问题：1）蛋白酶体ATPases的N末端域如何影响蛋白酶体函数？，2）哺乳动物P97如何刺激20S蛋白酶体的蛋白质降解？和3） PA28如何调节20S功能以催化核蛋白降解？我们选择专注于这三个监管机构，因为它们每个人都在降级的底物类型中扮演独特的角色，并且每个人都扮演关键角色在特定的人类疾病中。我们实施各种方法和系统来解决这些问题，包括研究古细菌，酵母，线虫，哺乳动物和人类的蛋白酶体调节剂的功能。此外，我们正在使用秀丽隐杆线虫作为动物模型系统来测试我们的生化模型和基因测试治疗概念。这项研究的成功完成将通过定义中心来对现场产生持续的影响这三种不同的细胞策略来确定蛋白质降解的机制，每种蛋白质降解都不同但是在生物学和疾病中的关键作用。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structure, Function, and Allosteric Regulation of the 20S Proteasome by the 11S/PA28 Family of Proteasome Activators.

DOI：
10.3390/biom13091326
发表时间：
2023-08-29
期刊：
Biomolecules
影响因子：
5.5
作者：
通讯作者：

Aortic dysfunction in metabolic syndrome mediated by perivascular adipose tissue TNFα- and NOX2-dependent pathway.

DOI：
10.1113/ep086818
发表时间：
2018-04-01
期刊：
Experimental physiology
影响因子：
2.7
作者：
DeVallance E;Branyan KW;Lemaster K;Olfert IM;Smith DM;Pistilli EE;Frisbee JC;Chantler PD
通讯作者：
Chantler PD

High resolution structures define divergent and convergent mechanisms of archaeal proteasome activation.