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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：
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.

项目总结/文摘

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

ATP binding to neighbouring subunits and intersubunit allosteric coupling underlie proteasomal ATPase function.