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Assembly, structure, and function of the 26S proteasome.

ABSTRACT: The 26S proteasome is a large multiprotein complex involved in the regulated degradation of ubiquitinated proteins in the cell. The 26S proteasome has been shown to control an increasing number of essential biochemical mechanisms of the cellular lifecycle including DNA synthesis, repair, transcription, translation, and cell signal transduction. Concurrently, it is increasingly seen that malfunction of the ubiquitin proteasome system contributes to the pathogenesis of disease. The recent identification of four molecular chaperones, in addition to five previously identified chaperones, have provided mechanistic insight into how this cellular megastructure is assembled in the cell. These data, together with new insights into the structure and function of the proteasome, provide a much better understanding of this complex protease.

SUBMITTER: Bedford L

PROVIDER: S-EPMC2902798 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Assembly, structure, and function of the 26S proteasome.

Bedford Lynn L Paine Simon S Sheppard Paul W PW Mayer R John RJ Roelofs Jeroen J

Trends in cell biology 20100426 7

The 26S proteasome is a large multiprotein complex involved in the regulated degradation of ubiquitinated proteins in the cell. The 26S proteasome has been shown to control an increasing number of essential biochemical mechanisms of the cellular lifecycle including DNA synthesis, repair, transcription, translation, and cell signal transduction. Concurrently, it is increasingly seen that malfunction of the ubiquitin proteasome system contributes to the pathogenesis of disease. The recent identifi ...[more]

PMID: 20427185

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Structure and Function of the 26S Proteasome.

Project description: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.

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Reversible phosphorylation of Rpn1 regulates 26S proteasome assembly and function.

Project description:The fundamental importance of the 26S proteasome in health and disease suggests that its function must be finely controlled, and yet our knowledge about proteasome regulation remains limited. Posttranslational modifications, especially phosphorylation, of proteasome subunits have been shown to impact proteasome function through different mechanisms, although the vast majority of proteasome phosphorylation events have not been studied. Here, we have characterized 1 of the most frequently detected proteasome phosphosites, namely Ser361 of Rpn1, a base subunit of the 19S regulatory particle. Using a variety of approaches including CRISPR/Cas9-mediated gene editing and quantitative mass spectrometry, we found that loss of Rpn1-S361 phosphorylation reduces proteasome activity, impairs cell proliferation, and causes oxidative stress as well as mitochondrial dysfunction. A screen of the human kinome identified several kinases including PIM1/2/3 that catalyze S361 phosphorylation, while its level is reversibly controlled by the proteasome-resident phosphatase, UBLCP1. Mechanistically, Rpn1-S361 phosphorylation is required for proper assembly of the 26S proteasome, and we have utilized a genetic code expansion system to directly demonstrate that S361-phosphorylated Rpn1 more readily forms a precursor complex with Rpt2, 1 of the first steps of 19S base assembly. These findings have revealed a prevalent and biologically important mechanism governing proteasome formation and function.

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Structure characterization of the 26S proteasome.

Project description:In all eukaryotic cells, 26S proteasome plays an essential role in the process of ATP-dependent protein degradation. In this review, we focus on structure characterization of the 26S proteasome. Although the progress towards a high-resolution structure of the 26S proteasome has been slow, the recently solved structures of various proteasomal subcomplexes have greatly enhanced our understanding of this large machinery. In addition to having an ATP-dependent proteolytic function, the 26S proteasome is also involved in many non-proteolytic cellular activities, which are often mediated by subunits in its 19S regulatory complex. Thus, we include a detailed discussion of the structures of 19S subunits, including proteasomal ATPases, ubiquitin receptors, deubiquitinating enzymes and subunits that contain PCI domain. This article is part of a Special Issue entitled The 26S Proteasome: When degradation is just not enough!

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N-Terminal Coiled-Coil Structure of ATPase Subunits of 26S Proteasome Is Crucial for Proteasome Function.

Project description:The proteasome is an essential proteolytic machine in eukaryotic cells, where it removes damaged proteins and regulates many cellular activities by degrading ubiquitinated proteins. Its heterohexameric AAA+ ATPase Rpt subunits play a central role in proteasome activity by the engagement of substrate unfolding and translocation for degradation; however, its detailed mechanism remains poorly understood. In contrast to AAA+ ATPase domains, their N-terminal regions of Rpt subunits substantially differ from each other. Here, to investigate the requirements and roles of the N-terminal regions of six Rpt subunits derived from Saccharomyces cerevisiae, we performed systematic mutational analysis using conditional knockdown yeast strains for each Rpt subunit and bacterial heterologous expression system of the base subcomplex. We showed that the formation of the coiled-coil structure was the most important for the N-terminal region of Rpt subunits. The primary role of coiled-coil structure would be the maintenance of the ring structure with the defined order. However, the coiled-coil region would be also be involved in substrate recognition and an interaction between lid and base subcomplexes.

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Reversible phosphorylation of Rpn1 regulates 26S proteasome assembly and function

2019-12-08 | PXD016643 |

Cryo-EM structure of the plant 26S proteasome.

Project description:Targeted proteolysis is a hallmark of life. It is especially important in long-lived cells that can be found in higher eukaryotes, like plants. This task is mainly fulfilled by the ubiquitin-proteasome system. Thus, proteolysis by the 26S proteasome is vital to development, immunity, and cell division. Although the yeast and animal proteasomes are well characterized, there is only limited information on the plant proteasome. We determined the first plant 26S proteasome structure from Spinacia oleracea by single-particle electron cryogenic microscopy at an overall resolution of 3.3 Å. We found an almost identical overall architecture of the spinach proteasome compared with the known structures from mammals and yeast. Nevertheless, we noticed a structural difference in the proteolytic active β1 subunit. Furthermore, we uncovered an unseen compression state by characterizing the proteasome's conformational landscape. We suspect that this new conformation of the 20S core protease, in correlation with a partial opening of the unoccupied gate, may contribute to peptide release after proteolysis. Our data provide a structural basis for the plant proteasome, which is crucial for further studies.

| S-EPMC9251434 | biostudies-literature

PSMD5 Inactivation Promotes 26S Proteasome Assembly during Colorectal Tumor Progression.

Project description:Protein degradation by the ubiquitin-proteasome system (UPS) is central to protein homeostasis and cell survival. The active 26S proteasome is a large protease complex consisting of a catalytic 20S subunit and 19S regulatory particles. Cancer cells are exposed to considerable protein overload due to high metabolic rates, reprogrammed energy metabolism, and aneuploidy. Here we report a mechanism that facilitates the assembly of active 26S proteasomes in malignant cells. Upon tumorigenic transformation of the gut epithelium, 26S proteasome assembly was significantly enhanced, but levels of individual subunits were not changed. This enhanced assembly of 26S proteasomes increased further with tumor progression and was observed specifically in transformed cells, but not in other rapidly dividing cells. Moreover, expression of PSMD5, an inhibitor of proteasome assembly, was reduced in intestinal tumors and silenced with tumor progression. Reexpression of PSMD5 in tumor cells caused decreased 26S assembly and accumulation of polyubiquitinated proteins. These results suggest that inhibition of cancer-associated proteasome assembly may provide a novel therapeutic strategy to selectively kill cancer cells.Significance: Enhanced cancer-associated proteasome assembly is a major stress response that allows tumors to adapt to and to withstand protein overload.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3458/F1.large.jpg Cancer Res; 78(13); 3458-68. ©2018 AACR.

| S-EPMC6030489 | biostudies-literature

Cryo-EM structure of the plant 26S proteasome

Project description: Not available

| EMPIAR-10974 | biostudies-other

Prostaglandin J2 alters gene expression patterns and 26S proteasome assembly in human neuroblastoma cells

Project description:Many neurodegenerative disorders are characterized by two pathological hallmarks: progressive loss of neurons and occurrence of inclusion bodies containing ubiquitinated proteins. The mechanisms responsible for these pathological features remain elusive. Inflammation may be critical to neurodegeneration associated with ubiquitin-protein aggregates. We previously showed that prostaglandin J2 (PGJ2), one of the endogenous products of inflammation, induces neuronal death and accumulation of ubiquitinated proteins into distinct aggregates. We now report that temporal microarray analysis of human neuroblastoma SK-N-SH cells treated with PGJ2 revealed changes relevant to neurodegeneration. PGJ2 triggered a “repair” response including increased expression of heat shock, protein folding, stress and cellular defense genes. PGJ2 also decreased expression of DNA repair genes and increased expression of apoptotic genes. Overtime pro-death responses prevailed over pro-survival responses, leading to cellular demise. Furthermore, PGJ2 increased the expression of proteasome and other ubiquitin-proteasome pathway genes. This increase failed to overcome PGJ2-inhibition of 26S proteasome activity. Ubiquitinated proteins are degraded by the 26S proteasome, shown here to be the most active proteasomal form in SK-N-SH cells. We demonstrate that PGJ2 impairs 26S proteasome assembly, which is an ATP-dependent process. Interestingly, PGJ2 is known to perturb mitochondrial function, which could be critical to the observed 26S proteasome disassembly and suggest a crosstalk between mitochondrial and proteasomal impairment. In conclusion neurotoxic products of inflammation, such as PGJ2, may play a role in neurodegenerative disorders associated with the aggregation of ubiquitinated proteins by impairing 26S proteasome activity and inducing a chain of events that culminates in neuronal cell death. Keywords: Drug response time course

2006-06-01 | GSE4329 | GEO

Proteasome Structure and Assembly.

Project description: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.

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