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Annual Review of Biochemistry Jun 2018As the endpoint for the ubiquitin-proteasome system, the 26S proteasome is the principal proteolytic machine responsible for regulated protein degradation in eukaryotic... (Review)
Review
As the endpoint for the ubiquitin-proteasome system, the 26S proteasome is the principal proteolytic machine responsible for regulated protein degradation in eukaryotic cells. The proteasome's cellular functions range from general protein homeostasis and stress response to the control of vital processes such as cell division and signal transduction. To reliably process all the proteins presented to it in the complex cellular environment, the proteasome must combine high promiscuity with exceptional substrate selectivity. Recent structural and biochemical studies have shed new light on the many steps involved in proteasomal substrate processing, including recognition, deubiquitination, and ATP-driven translocation and unfolding. In addition, these studies revealed a complex conformational landscape that ensures proper substrate selection before the proteasome commits to processive degradation. These advances in our understanding of the proteasome's intricate machinery set the stage for future studies on how the proteasome functions as a major regulator of the eukaryotic proteome.
Topics: ATPases Associated with Diverse Cellular Activities; Deubiquitinating Enzymes; Humans; Models, Biological; Models, Molecular; Molecular Motor Proteins; Proteasome Endopeptidase Complex; Protein Conformation; Saccharomyces cerevisiae Proteins; Substrate Specificity; Ubiquitin
PubMed: 29652515
DOI: 10.1146/annurev-biochem-062917-011931 -
Cell May 2017The ubiquitin proteasome pathway is responsible for most of the protein degradation in mammalian cells. Rates of degradation by this pathway have generally been assumed... (Review)
Review
The ubiquitin proteasome pathway is responsible for most of the protein degradation in mammalian cells. Rates of degradation by this pathway have generally been assumed to be determined by rates of ubiquitylation. However, recent studies indicate that proteasome function is also tightly regulated and determines whether a ubiquitylated protein is destroyed or deubiquitylated and survives longer. This article reviews recent advances in our understanding of the proteasome's multistep ATP-dependent mechanism, its biochemical and structural features that ensure efficient proteolysis and ubiquitin recycling while preventing nonselective proteolysis, and the regulation of proteasome activity by interacting proteins and subunit modifications, especially phosphorylation.
Topics: Adenosine Triphosphatases; Allosteric Regulation; Animals; Eukaryota; Humans; Phosphorylation; Proteasome Endopeptidase Complex; Proteolysis; Ubiquitination
PubMed: 28525752
DOI: 10.1016/j.cell.2017.04.023 -
Cellular and Molecular Life Sciences :... Dec 2014In eukaryotic cells, proteasomes are highly conserved protease complexes and eliminate unwanted proteins which are marked by poly-ubiquitin chains for degradation. The... (Review)
Review
In eukaryotic cells, proteasomes are highly conserved protease complexes and eliminate unwanted proteins which are marked by poly-ubiquitin chains for degradation. The 26S proteasome consists of the proteolytic core particle, the 20S proteasome, and the 19S regulatory particle, which are composed of 14 and 19 different subunits, respectively. Proteasomes are the second-most abundant protein complexes and are continuously assembled from inactive precursor complexes in proliferating cells. The modular concept of proteasome assembly was recognized in prokaryotic ancestors and applies to eukaryotic successors. The efficiency and fidelity of eukaryotic proteasome assembly is achieved by several proteasome-dedicated chaperones that initiate subunit incorporation and control the quality of proteasome assemblies by transiently interacting with proteasome precursors. It is important to understand the mechanism of proteasome assembly as the proteasome has key functions in the turnover of short-lived proteins regulating diverse biological processes.
Topics: Animals; Humans; Models, Biological; Models, Molecular; Proteasome Endopeptidase Complex; Protein Binding; Protein Conformation; Protein Subunits
PubMed: 25107634
DOI: 10.1007/s00018-014-1699-8 -
Biochimica Et Biophysica Acta Jan 2014Proteasomes are highly conserved multisubunit protease complexes and occur in the cyto- and nucleoplasm of eukaryotic cells. In dividing cells proteasomes exist as... (Review)
Review
Proteasomes are highly conserved multisubunit protease complexes and occur in the cyto- and nucleoplasm of eukaryotic cells. In dividing cells proteasomes exist as holoenzymes and primarily localize in the nucleus. During quiescence they dissociate into proteolytic core and regulatory complexes and are sequestered into motile cytosolic clusters. Proteasome clusters rapidly clear upon the exit from quiescence, where proteasome core and regulatory complexes reassemble and localize to the nucleus again. The mechanisms underlying proteasome transport and assembly are not yet understood. Here, I summarize our present knowledge about nuclear transport and assembly of proteasomes in yeast and project our studies in this eukaryotic model organism to the mammalian cell system. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.
Topics: Active Transport, Cell Nucleus; Animals; Cell Division; Cell Nucleus; Genetic Variation; Humans; Kinetics; Models, Molecular; Proteasome Endopeptidase Complex
PubMed: 23545412
DOI: 10.1016/j.bbamcr.2013.03.023 -
Journal of Molecular Biology Nov 2017The eukaryotic 26S proteasome is a large multisubunit complex that degrades the majority of proteins in the cell under normal conditions. The 26S proteasome can be... (Review)
Review
The eukaryotic 26S proteasome is a large multisubunit complex that degrades the majority of proteins in the cell under normal conditions. The 26S proteasome can be divided into two subcomplexes: the 19S regulatory particle and the 20S core particle. Most substrates are first covalently modified by ubiquitin, which then directs them to the proteasome. The function of the regulatory particle is to recognize, unfold, deubiquitylate, and translocate substrates into the core particle, which contains the proteolytic sites of the proteasome. Given the abundance and subunit complexity of the proteasome, the assembly of this ~2.5MDa complex must be carefully orchestrated to ensure its correct formation. In recent years, significant progress has been made in the understanding of proteasome assembly, structure, and function. Technical advances in cryo-electron microscopy have resulted in a series of atomic cryo-electron microscopy structures of both human and yeast 26S proteasomes. These structures have illuminated new intricacies and dynamics of the proteasome. In this review, we focus on the mechanisms of proteasome assembly, particularly in light of recent structural information.
Topics: Cryoelectron Microscopy; Eukaryotic Cells; Proteasome Endopeptidase Complex; Protein Multimerization
PubMed: 28583440
DOI: 10.1016/j.jmb.2017.05.027 -
Biochimica Et Biophysica Acta Jan 2014Most proteasome substrates are marked for degradation by ubiquitin conjugation, but some are targeted by other means. The properties of these exceptional cases provide... (Review)
Review
Most proteasome substrates are marked for degradation by ubiquitin conjugation, but some are targeted by other means. The properties of these exceptional cases provide insights into the general requirements for proteasomal degradation. Here the focus is on three ubiquitin-independent substrates that have been the subject of detailed study. These are Rpn4, a transcriptional regulator of proteasome homeostasis, thymidylate synthase, an enzyme required for production of DNA precursors and ornithine decarboxylase, the initial enzyme committed to polyamine biosynthesis. It can be inferred from these cases that proteasome association and the presence of an unstructured region are the sole prerequisites for degradation. Based on that inference, artificial substrates have been designed to test the proteasome's capacity for substrate processing and its limitations. Ubiquitin-independent substrates may in some cases be a remnant of the pre-ubiquitome world, but in other cases could provide optimized regulatory solutions. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.
Topics: Animals; DNA-Binding Proteins; Humans; Ornithine Decarboxylase; Proteasome Endopeptidase Complex; Protein Structure, Tertiary; Protein Unfolding; Proteolysis; Saccharomyces cerevisiae Proteins; Thymidylate Synthase; Transcription Factors; Ubiquitin
PubMed: 23684952
DOI: 10.1016/j.bbamcr.2013.05.008 -
Biomolecules Jun 2014Proteasomes are key proteases involved in a variety of processes ranging from the clearance of damaged proteins to the presentation of antigens to CD8+ T-lymphocytes.... (Review)
Review
Proteasomes are key proteases involved in a variety of processes ranging from the clearance of damaged proteins to the presentation of antigens to CD8+ T-lymphocytes. Which cleavage sites are used within the target proteins and how fast these proteins are degraded have a profound impact on immune system function and many cellular metabolic processes. The regulation of proteasome activity involves different mechanisms, such as the substitution of the catalytic subunits, the binding of regulatory complexes to proteasome gates and the proteasome conformational modifications triggered by the target protein itself. Mathematical models are invaluable in the analysis; and potentially allow us to predict the complex interactions of proteasome regulatory mechanisms and the final outcomes of the protein degradation rate and MHC class I epitope generation. The pioneering attempts that have been made to mathematically model proteasome activity, cleavage preference variation and their modification by one of the regulatory mechanisms are reviewed here.
Topics: Animals; Humans; Hydrolysis; Models, Biological; Oligopeptides; Proteasome Endopeptidase Complex
PubMed: 24970232
DOI: 10.3390/biom4020585 -
Cell Chemical Biology Jun 2017While proteasome inhibitors are now well-established research tools and chemotherapeutics, proteasome activators are much less explored. In this issue of Cell Chemical...
While proteasome inhibitors are now well-established research tools and chemotherapeutics, proteasome activators are much less explored. In this issue of Cell Chemical Biology, in a study from the groups of Berkers and Ovaa (Leestemaker et al., 2017), a chemical screen was used to identify a p38 MAPK inhibitor as a proteasome activator. This compound furthermore enhanced clearance of protein aggregates, thereby implicating alternative chemotherapeutic options for treating neurodegenerative diseases.
Topics: Enzyme Activation; Proteasome Endopeptidase Complex; Proteasome Inhibitors; p38 Mitogen-Activated Protein Kinases
PubMed: 28644955
DOI: 10.1016/j.chembiol.2017.06.005 -
Annual Review of Microbiology 2015Interest in bacterial proteasomes was sparked by the discovery that proteasomal degradation is required for the pathogenesis of Mycobacterium tuberculosis, one of the... (Review)
Review
Interest in bacterial proteasomes was sparked by the discovery that proteasomal degradation is required for the pathogenesis of Mycobacterium tuberculosis, one of the world's deadliest pathogens. Although bacterial proteasomes are structurally similar to their eukaryotic and archaeal homologs, there are key differences in their mechanisms of assembly, activation, and substrate targeting for degradation. In this article, we compare and contrast bacterial proteasomes with their archaeal and eukaryotic counterparts, and we discuss recent advances in our understanding of how bacterial proteasomes function to influence microbial physiology.
Topics: Archaea; Bacterial Proteins; Eukaryotic Cells; Mycobacterium; Mycobacterium tuberculosis; Proteasome Endopeptidase Complex; Proteolysis
PubMed: 26488274
DOI: 10.1146/annurev-micro-091014-104201 -
Biomolecules Apr 2022Proteasomes are traditionally considered intracellular complexes that play a critical role in maintaining proteostasis by degrading short-lived regulatory proteins and... (Review)
Review
Proteasomes are traditionally considered intracellular complexes that play a critical role in maintaining proteostasis by degrading short-lived regulatory proteins and removing damaged proteins. Remarkably, in addition to these well-studied intracellular roles, accumulating data indicate that proteasomes are also present in extracellular body fluids. Not much is known about the origin, biological role, mode(s) of regulation or mechanisms of extracellular transport of these complexes. Nevertheless, emerging evidence indicates that the presence of proteasomes in the extracellular milieu is not a random phenomenon, but rather a regulated, coordinated physiological process. In this review, we provide an overview of the current understanding of extracellular proteasomes. To this end, we examine 143 proteomic datasets, leading us to the realization that 20S proteasome subunits are present in at least 25 different body fluids. Our analysis also indicates that while 19S subunits exist in some of those fluids, the dominant proteasome activator in these compartments is the PA28α/β complex. We also elaborate on the positive correlations that have been identified in plasma and extracellular vesicles, between 20S proteasome and activity levels to disease severity and treatment efficacy, suggesting the involvement of this understudied complex in pathophysiology. In addition, we address the considerations and practical experimental methods that should be taken when investigating extracellular proteasomes. Overall, we hope this review will stimulate new opportunities for investigation and thoughtful discussions on this exciting topic that will contribute to the maturation of the field.
Topics: Cytoplasm; Extracellular Vesicles; Proteasome Endopeptidase Complex; Proteins; Proteomics
PubMed: 35625547
DOI: 10.3390/biom12050619