Mechanisms regulating proteasomal substrate degradation

蛋白酶体底物降解的调节机制

• 批准号: 10022500
• 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
• 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/10022500
• 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

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 从本质上讲，每个酒窖的过程。 导致疾病，例如神经变性和癌症。 与神经退行性疾病相关的堆积可能会损害UPS，加剧 疾病实际上。 神经退行性疾病相反，在肿瘤疾病中。 这是多发性骨髓瘤的第一线治疗方法是蛋白酶体的抑制作用。 在这两种主要的人类疾病中的位置。 由非常不同的调节络合物（例如19s，PA28，PA200和推定的P97）。 复合物是调节蛋白酶体的核心粒子，即20s，分离物是蛋白质降解 来自蜂窝环境的腔室。 20S蛋白酶体基材门，将底部暴露于内部降解室 它的监管机构提供了丰富的监管景观，以开发出可能会对这两个大型领域产生深远影响 研究 蛋白酶体结构有助于这项工作，但结构是通过理解动态机制的结构 其功能是有限的。 多种蛋白酶体复合物的功能，并防止Y调节蛋白质降解 专注于特定问题：1）蛋白酶体呼吸器的N末端域如何影响原季 函数？，2）哺乳动物P97如何通过20S蛋白酶体降解降解？和3） PA28常规20s如何催化核蛋白降解？ 监管机构，因为它们每个人都在降级的基础基础基础类型中扮演独特的角色，并且它们扮演着关键角色 在特定的人类疾病中。 研究来自Archea，酵母，线虫，哺乳动物和人类的蛋白酶体调节剂的功能。 是否使用秀丽隐杆线虫作为动物模型系统来测试我们的生化衍生模型和遗传测试测试Teutic 概念，通过定义中心，成功地压缩了现场的持续影响。 三种不同的细胞策略的机制 但是在生物学和疾病中的关键作用。