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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：
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/10247747
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，本提案主要侧重于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，包括研究古细菌、酵母、线虫、哺乳动物和人类的蛋白酶体调节因子的功能。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。