Proteasome - Knowledge

757:. Interestingly, this structure also shows how the DUB activity is coupled to the substrate recognition by the proteasomal AAA-ATPase. In contrast to Rpn11, USP14 and UCH37 are the DUBs that do not always associated with the proteasome. In cells, about 10-40% of the proteasomes were found to have USP14 associated. Both Ubp6/USP14 and UCH37 are largely activated by the proteasome and exhibit a very low DUB activity alone. Once activated, USP14 was found to suppress proteasome function by its DUB activity and by inducing parallel pathways of proteasome conformational transitions, one of which turned out to directly prohibit substrate insertion into the AAA-ATPase, as intuitively observed by time-resolved cryogenic electron microscopy. It appears that USP14 regulates proteasome function at multiple checkpoints by both catalytically competing with Rpn11 and allosterically reprogramming the AAA-ATPase states, which is rather unexpected for a DUB. These observations imply that the proteasome regulation may depend on its dynamic transitions of conformational states. 888:. Degradation occurs within the central chamber formed by the association of the two β rings and normally does not release partially degraded products, instead reducing the substrate to short polypeptides typically 7–9 residues long, though they can range from 4 to 25 residues, depending on the organism and substrate. The biochemical mechanism that determines product length is not fully characterized. Although the three catalytic β subunits have a common mechanism, they have slightly different substrate specificities, which are considered chymotrypsin-like, trypsin-like, and peptidyl-glutamyl peptide-hydrolyzing (PHGH)-like. These variations in specificity are the result of interatomic contacts with local residues near the active sites of each subunit. Each catalytic β subunit also possesses a conserved lysine residue required for proteolysis. 443:

homolog of these ATPases exists in archaea, called PAN (proteasome-activating nucleotidase). The association of the 19S and 20S particles requires the binding of ATP to the 19S ATPase subunits, and ATP hydrolysis is required for the assembled complex to degrade folded and ubiquitinated proteins. Note that only the step of substrate unfolding requires energy from ATP hydrolysis, while ATP-binding alone can support all the other steps required for protein degradation (e.g., complex assembly, gate opening, translocation, and proteolysis). In fact, ATP binding to the ATPases by itself supports the rapid degradation of unfolded proteins. However, while ATP hydrolysis is required for unfolding only, it is not yet clear whether this energy may be used in the coupling of some of these steps.

462:) that assemble to a heterohexameric ring of the order Rpt1/Rpt2/Rpt6/Rpt3/Rpt4/Rpt5. This ring is a trimer of dimers: Rpt1/Rpt2, Rpt6/Rpt3, and Rpt4/Rpt5 dimerize via their N-terminal coiled-coils. These coiled-coils protrude from the hexameric ring. The largest regulatory particle non-ATPases Rpn1 and Rpn2 bind to the tips of Rpt1/2 and Rpt6/3, respectively. The ubiquitin receptor Rpn13 binds to Rpn2 and completes the base sub-complex. The lid covers one half of the AAA-ATPase hexamer (Rpt6/Rpt3/Rpt4) and, unexpectedly, directly contacts the 20S via Rpn6 and to lesser extent Rpn5. The subunits Rpn9, Rpn5, Rpn6, Rpn7, Rpn3, and Rpn12, which are structurally related among themselves and to subunits of the 510:(i.e., HbYX motif). The ATPases C-termini bind into pockets in the top of the 20S, and tether the ATPase complex to the 20S proteolytic complex, thus joining the substrate unfolding equipment with the 20S degradation machinery. Binding of these C-termini into these 20S pockets by themselves stimulates opening of the gate in the 20S in much the same way that a "key-in-a-lock" opens a door. The precise mechanism by which this "key-in-a-lock" mechanism functions has been structurally elucidated in the context of human 26S proteasome at near-atomic resolution, suggesting that the insertion of five C-termini of ATPase subunits Rpt1/2/3/5/6 into the 20S surface pockets are required to fully open the 20S gate. 434:, whose substrate specificity is altered relative to the normal proteasome. Recently an alternative proteasome was identified in human cells that lack the α3 core subunit. These proteasomes (known as the α4-α4 proteasomes) instead form 20S core particles containing an additional α4 subunit in place of the missing α3 subunit. These alternative 'α4-α4' proteasomes have been known previously to exist in yeast. Although the precise function of these proteasome isoforms is still largely unknown, cells expressing these proteasomes show enhanced resistance to toxicity induced by metallic ions such as cadmium. 492: 488:

structural changes of the AAA-ATPase module. Some of the substrate-bound conformations bear high similarity to the substrate-free ones, but they are not entirely identical, particularly in the AAA-ATPase module. Prior to the 26S assembly, the 19S regulatory particle in a free form has also been observed in seven conformational states. Notably, all these conformers are somewhat different and present distinct features. Thus, the 19S regulatory particle can sample at least 20 conformational states under different physiological conditions.

458:. In 2016, three independent efforts have determined the first near-atomic resolution structure of the human 26S proteasome in the absence of substrates by cryo-EM. In 2018, a major effort has elucidated the detailed mechanisms of deubiquitylation, initiation of translocation and processive unfolding of substrates by determining seven atomic structures of substrate-engaged 26S proteasome simultaneously. In the heart of the 19S, directly adjacent to the 20S, are the AAA-ATPases ( 447: 303: 22: 1482: 1297:. Oxidized proteins, which often form large amorphous aggregates in the cell, can be degraded directly by the 20S core particle without the 19S regulatory cap and do not require ATP hydrolysis or tagging with ubiquitin. However, high levels of oxidative damage increases the degree of cross-linking between protein fragments, rendering the aggregates resistant to proteolysis. Larger numbers and sizes of such highly oxidized aggregates are associated with 838: 31: 372:) form a gate that blocks unregulated access of substrates to the interior cavity. The inner two rings each consist of seven β subunits and in their N-termini contain the protease active sites that perform the proteolysis reactions. Three distinct catalytic activities were identified in the purified complex: chymotrypsin-like, trypsin-like and peptidylglutamyl-peptide hydrolyzing. The size of the proteasome is relatively conserved and is about 150 1888: 627: 1380:, are the primary producers of peptides which are optimal in size and composition for MHC binding. These proteins whose expression increases during the immune response include the 11S regulatory particle, whose main known biological role is regulating the production of MHC ligands, and specialized β subunits called β1i, β2i, and β5i with altered substrate specificity. The complex formed with the specialized β subunits is known as the 736: 244:, a protein that had no known function. It was then discovered that a previously identified protein associated with proteolytic degradation, known as ATP-dependent proteolysis factor 1 (APF-1), was the same protein as ubiquitin. The proteolytic activities of this system were isolated as a multi-protein complex originally called the multi-catalytic proteinase complex by Sherwin Wilk and Marion Orlowski. Later, the 1463: 950: 753:

in cells. Rpn11 is an intrinsic, stoichiometric subunit of the 19S regulatory particle and is essential for the function of 26S proteasome. The DUB activity of Rpn11 is enhanced in the proteasome as compared to its monomeric form. How Rpn11 removes a ubiquitin chain en bloc from a protein substrate was captured by an atomic structure of the substrate-engaged human proteasome in a conformation named E

1188:, but the proteasome also plays important and diverse roles in the apoptotic process. The involvement of the proteasome in this process is indicated by both the increase in protein ubiquitination, and of E1, E2, and E3 enzymes that is observed well in advance of apoptosis. During apoptosis, proteasomes localized to the nucleus have also been observed to translocate to outer membrane 1038:. Mitotic cyclins, which persist in the cell for only a few minutes, have one of the shortest life spans of all intracellular proteins. After a CDK-cyclin complex has performed its function, the associated cyclin is polyubiquitinated and destroyed by the proteasome, which provides directionality for the cell cycle. In particular, exit from 680:(E3) recognizes the specific protein to be ubiquitinated and catalyzes the transfer of ubiquitin from E2 to this target protein. A target protein must be labeled with at least four ubiquitin monomers (in the form of a polyubiquitin chain) before it is recognized by the proteasome lid. It is therefore the E3 that confers 1554:. Lactacystin covalently modifies the amino-terminal threonine of catalytic β subunits of the proteasome, particularly the β5 subunit responsible for the proteasome's chymotrypsin-like activity. This discovery helped to establish the proteasome as a mechanistically novel class of protease: an amino-terminal 1168:

expression. The cellular consequences of ARF activation depend on the plant type and developmental stage, but are involved in directing growth in roots and leaf veins. The specific response to ARF derepression is thought to be mediated by specificity in the pairing of individual ARF and Aux/IAA proteins.

899:, are synthesized as inactive precursors whose ubiquitination and subsequent proteasomal degradation converts them to an active form. Such activity requires the proteasome to cleave the substrate protein internally, rather than processively degrading it from one terminus. It has been suggested that long 774:

in the overall proteolysis reaction depends on the specific substrate; for some proteins, the unfolding process is rate-limiting, while deubiquitination is the slowest step for other proteins. The extent to which substrates must be unfolded before translocation is suggested to be around 20 amino acid

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Ubiquitin chains conjugated to a protein targeted for proteasomal degradation are normally removed by any one of the three proteasome-associated deubiquitylating enzymes (DUBs), which are Rpn11, Ubp6/USP14 and UCH37. This process recycles ubiquitin and is essential to maintain the ubiquitin reservoir

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Proteasome inhibition has different effects on apoptosis induction in different cell types. In general, the proteasome is not required for apoptosis, although inhibiting it is pro-apoptotic in most cell types that have been studied. Apoptosis is mediated through disrupting the regulated degradation

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protein identified to date. Ubiquitin contains seven lysine residues to which another ubiquitin can be ligated, resulting in different types of polyubiquitin chains. Chains in which each additional ubiquitin is linked to lysine 48 of the previous ubiquitin have a role in proteasome targeting, while

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and ubiquitin binding sites; it is this structure that recognizes polyubiquitinated proteins and transfers them to the catalytic core. An alternative form of regulatory subunit called the 11S particle can associate with the core in essentially the same manner as the 19S particle; the 11S may play a

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O'Connor OA, Wright J, Moskowitz C, Muzzy J, MacGregor-Cortelli B, Stubblefield M, Straus D, Portlock C, Hamlin P, Choi E, Dumetrescu O, Esseltine D, Trehu E, Adams J, Schenkein D, Zelenetz AD (February 2005). "Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients

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After a protein has been ubiquitinated, it is recognized by the 19S regulatory particle in an ATP-dependent binding step. The substrate protein must then enter the interior of the 20S subunit to come in contact with the proteolytic active sites. Because the 20S particle's central channel is narrow

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The 19S regulatory particle is responsible for stimulating the 20S to degrade proteins. A primary function of the 19S regulatory ATPases is to open the gate in the 20S that blocks the entry of substrates into the degradation chamber. The mechanism by which the proteasomal ATPase open this gate has

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The 19S regulatory particle within the 26S proteasome holoenzyme has been observed in six strongly differing conformational states in the absence of substrates to date. A hallmark of the AAA-ATPase configuration in this predominant low-energy state is a staircase- or lockwasher-like arrangement of

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The number and diversity of subunits contained in the 20S core particle depends on the organism; the number of distinct and specialized subunits is larger in multicellular than unicellular organisms and larger in eukaryotes than in prokaryotes. All 20S particles consist of four stacked heptameric

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containing one 20S protein subunit and two 19S regulatory cap subunits. The core is hollow and provides an enclosed cavity in which proteins are degraded; openings at the two ends of the core allow the target protein to enter. Each end of the core particle associates with a 19S regulatory subunit

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repressors known as Aux/IAA proteins for proteasomal degradation. These proteins are ubiquitinated by SCFTIR1, or SCF in complex with the auxin receptor TIR1. Degradation of Aux/IAA proteins derepresses transcription factors in the auxin-response factor (ARF) family and induces ARF-directed gene

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have been shown to inhibit substrate unfolding, decreasing the efficiency of proteasomal degradation; this results in the release of partially degraded byproducts, possibly due to the decoupling of the ATP hydrolysis and unfolding steps. Such glycine-alanine repeats are also found in nature, for

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but absence of substrate three alternative, less abundant conformations of the 19S are adopted primarily differing in the positioning of the lid with respect to the AAA-ATPase module. In the presence of ATP-γS or a substrate, considerably more conformations have been observed displaying dramatic

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The 19S particle in eukaryotes consists of 19 individual proteins and is divisible into two subassemblies, a 9-subunit base that binds directly to the α ring of the 20S core particle, and a 10-subunit lid. Six of the nine base proteins are ATPase subunits from the AAA Family, and an evolutionary

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patches on the surface of misfolded proteins and recruits E3 ubiquitin ligases such as CHIP to tag the proteins for proteasomal degradation. The CHIP protein (carboxyl terminus of Hsp70-interacting protein) is itself regulated via inhibition of interactions between the E3 enzyme CHIP and its E2

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The mechanism by which a polyubiquitinated protein is targeted to the proteasome is not fully understood. A few high-resolution snapshots of the proteasome bound to a polyubiquitinated protein suggest that ubiquitin receptors might be coordinated with deubiquitinase Rpn11 for initial substrate

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damages the proteasome's ability to assemble. The assembly of the half-proteasomes, in turn, is initiated by the assembly of the α subunits into their heptameric ring, forming a template for the association of the corresponding pro-β ring. The assembly of α subunits has not been characterized.

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during the assembly of the 20S particle to expose the proteolytic active site. The 20S particle is assembled from two half-proteasomes, each of which consists of a seven-membered pro-β ring attached to a seven-membered α ring. The association of the β rings of the two half-proteasomes triggers

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Tarrason Risa, Gabriel; Hurtig, Fredrik; Bray, Sian; Hafner, Anne E.; Harker-Kirschneck, Lena; Faull, Peter; Davis, Colin; Papatziamou, Dimitra; Mutavchiev, Delyan R.; Fan, Catherine; Meneguello, Leticia; Arashiro Pulschen, Andre; Dey, Gautam; Culley, Siân; Kilkenny, Mairi; Souza, Diorge P.;

1744:. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of 1669:

The proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic

474:, is placed at the mouth of the AAA-ATPase hexamer, ideally positioned to remove ubiquitin moieties immediately before translocation of substrates into the 20S. The second ubiquitin receptor identified to date, Rpn10, is positioned at the periphery of the lid, near subunits Rpn8 and Rpn9. 1693:. Proteasome defects lead to reduced proteolytic activity and the accumulation of damaged or misfolded proteins, which may contribute to neurodegenerative disease, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to 1670:

interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.

995:, whose gene products are a multimeric protease arranged in a two-layered ring and an ATPase. The hslV protein has been hypothesized to resemble the likely ancestor of the 20S proteasome. In general, HslV is not essential in bacteria, and not all bacteria possess it, whereas some 534:

but not of complete proteins. It is presumed that this is because the complex cannot unfold larger substrates. This structure is also known as PA28, REG, or PA26. The mechanisms by which it binds to the core particle through the C-terminal tails of its subunits and induces α-ring

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have also been reported, although p53 is also subject to ubiquitin-dependent degradation. Finally, structurally abnormal, misfolded, or highly oxidized proteins are also subject to ubiquitin-independent and 19S-independent degradation under conditions of cellular stress.

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Verdoes M, Florea BI, Menendez-Benito V, Maynard CJ, Witte MD, van der Linden WA, van den Nieuwendijk AM, Hofmann T, Berkers CR, van Leeuwen FW, Groothuis TA, Leeuwenburgh MA, Ovaa H, Neefjes JJ, Filippov DV, van der Marel GA, Dantuma NP, Overkleeft HS (November 2006).

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ring. To date it is still under debate whether the base complex assembles separately, whether the assembly is templated by the 20S core particle, or whether alternative assembly pathways exist. In addition to the four assembly chaperones, the deubiquitinating enzyme

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Only recently, the assembly process of the 19S regulatory particle has been elucidated to considerable extent. The 19S regulatory particle assembles as two distinct subcomponents, the base and the lid. Assembly of the base complex is facilitated by four assembly

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homologous to β subunits. They are assembled with their N-termini adjacent to that of the β subunits. The outer two rings in the stack consist of seven α subunits each, which serve as docking domains for the regulatory particles and the alpha subunits N-termini

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specificity to this system. The number of E1, E2, and E3 proteins expressed depends on the organism and cell type, but there are many different E3 enzymes present in humans, indicating that there is a huge number of targets for the ubiquitin proteasome system.

1216: — are prevented from undergoing apoptosis on exposure to proteasome inhibitors. The mechanism for this effect is not clear, but is hypothesized to be specific to cells in quiescent states, or to result from the differential activity of the pro-apoptotic 495:

Three distinct conformational states of the 26S proteasome. The conformations are hypothesized to be responsible for recruitment of the substrate, its irreversible commitment, and finally processing and translocation into the core particle, where degradation

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to open the 20S gate suggest a similar mechanism for the 19S particle. The expression of the 11S particle is induced by interferon gamma and is responsible, in conjunction with the immunoproteasome β subunits, for the generation of peptides that bind to the

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on these proteins' surfaces serve as the proteasomal substrates and enter the central cavity, while the majority of the protein remains outside. Similar effects have been observed in yeast proteins; this mechanism of selective degradation is known as

1592:. Clinical results also seem to justify use of proteasome inhibitor combined with chemotherapy, for B-cell acute lymphoblastic leukemia Proteasome inhibitors can kill some types of cultured leukemia cells that are resistant to glucocorticoids. 221:, which lack lysosomes, suggested the presence of a second intracellular degradation mechanism. This was shown in 1978 to be composed of several distinct protein chains, a novelty among proteases at the time. Later work on modification of 25:

Cartoon representation of a proteasome. Its active sites are sheltered inside the tube (blue). The caps (red; in this case, 11S regulatory particles) on the ends regulate entry into the destruction chamber, where the protein is

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and by close contacts with a region called the "B pocket" on the MHC surface. Many MHC class I alleles prefer hydrophobic C-terminal residues, and the immunoproteasome complex is more likely to generate hydrophobic C-termini.

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Lambrou GI, Papadimitriou L, Chrousos GP, Vlahopoulos SA (April 2012). "Glucocorticoid and proteasome inhibitor impact on the leukemic lymphoblast: multiple, diverse signals converging on a few key downstream regulators".

1820:). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory 1097:) are the two key regulators of cyclin degradation and checkpoint control; the SCF itself is regulated by the APC via ubiquitination of the adaptor protein, Skp2, which prevents SCF activity before the G1-S transition. 8130:

Egerer K, Kuckelkorn U, Rudolph PE, Rückert JC, Dörner T, Burmester GR, Kloetzel PM, Feist E (October 2002). "Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases".

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Schematic diagram of the proteasome 20S core particle viewed from one side. The α subunits that make up the outer two rings are shown in green, and the β subunits that make up the inner two rings are shown in

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Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S, Elliott PJ (June 1999). "Proteasome inhibitors: a novel class of potent and effective antitumor agents".

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before translocation. While energy is needed for substrate unfolding, it is not required for translocation. The assembled 26S proteasome can degrade unfolded proteins in the presence of a non-hydrolyzable

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20S proteasomes can also associate with a second type of regulatory particle, the 11S regulatory particle, a heptameric structure that does not contain any ATPases and can promote the degradation of short

1546:, was the first non-peptidic proteasome inhibitor discovered and is widely used as a research tool in biochemistry and cell biology. Lactacystin was licensed to Myogenics/Proscript, which was acquired by 1006:

Sequence analysis suggests that the catalytic β subunits diverged earlier in evolution than the predominantly structural α subunits. In bacteria that express a 20S proteasome, the β subunits have high

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and gated by the N-terminal tails of the α ring subunits, the substrates must be at least partially unfolded before they enter the core. The passage of the unfolded substrate into the core is called

376:(Å) by 115 Å. The interior chamber is at most 53 Å wide, though the entrance can be as narrow as 13 Å, suggesting that substrate proteins must be at least partially unfolded to enter. 138:, the proteasome is a cylindrical complex containing a "core" of four stacked rings forming a central pore. Each ring is composed of seven individual proteins. The inner two rings are made of seven 790:

The gate formed by the α subunits prevents peptides longer than about four residues from entering the interior of the 20S particle. The ATP molecules bound before the initial recognition step are

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Manaka H, Kato T, Kurita K, Katagiri T, Shikama Y, Kujirai K, Kawanami T, Suzuki Y, Nihei K, Sasaki H (May 1992). "Marked increase in cerebrospinal fluid ubiquitin in Creutzfeldt–Jakob disease".

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Gille C, Goede A, Schlöetelburg C, Preissner R, Kloetzel PM, Göbel UB, Frömmel C (March 2003). "A comprehensive view on proteasomal sequences: implications for the evolution of the proteasome".

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by disrupting the regulated degradation of pro-growth cell cycle proteins. This approach of selectively inducing apoptosis in tumor cells has proven effective in animal models and human trials.

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Although most proteasomal substrates must be ubiquitinated before being degraded, there are some exceptions to this general rule, especially when the proteasome plays a normal role in the post-

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Fenteany G, Standaert RF, Lane WS, Choi S, Corey EJ, Schreiber SL (May 1995). "Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin".

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Sharma N, Brandis KA, Herrera SK, Johnson BE, Vaidya T, Shrestha R, Debburman SK (2006). "alpha-Synuclein budding yeast model: toxicity enhanced by impaired proteasome and oxidative stress".

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Ikeda K, Akiyama H, Arai T, Ueno H, Tsuchiya K, Kosaka K (July 2002). "Morphometrical reappraisal of motor neuron system of Pick's disease and amyotrophic lateral sclerosis with dementia".

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Shah SA, Potter MW, McDade TP, Ricciardi R, Perugini RA, Elliott PJ, Adams J, Callery MP (2001). "26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer".

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Pitzer F, Dantes A, Fuchs T, Baumeister W, Amsterdam A (September 1996). "Removal of proteasomes from the nucleus and their accumulation in apoptotic blebs during programmed cell death".

5937:"Expression of a 26S proteasome ATPase subunit, MS73, in muscles that undergo developmentally programmed cell death, and its control by ecdysteroid hormones in the insect Manduca sexta" 154:

that recognize polyubiquitin tags attached to protein substrates and initiate the degradation process. The overall system of ubiquitination and proteasomal degradation is known as the

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Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, Epner E, Krishnan A, Leonard JP, Lonial S, Stadtmauer EA, O'Connor OA, Shi H, Boral AL, Goy A (October 2006).

799:, but cannot degrade folded proteins, indicating that energy from ATP hydrolysis is used for substrate unfolding. Passage of the unfolded substrate through the opened gate occurs via 146:. These sites are located on the interior surface of the rings, so that the target protein must enter the central pore before it is degraded. The outer two rings each contain seven 6718:

Jakob C, Egerer K, Liebisch P, Türkmen S, Zavrski I, Kuckelkorn U, Heider U, Kaiser M, Fleissner C, Sterz J, Kleeberg L, Feist E, Burmester GR, Kloetzel PM, Sezer O (March 2007).

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are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as

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Pellegrini, Luca; de Bruin, Robertus A. M.; Henriques, Ricardo; Snijders, Ambrosius P.; Šarić, Anđela; Lindås, Ann-Christin; Robinson, Nicholas P.; Baum, Buzz (7 August 2020).

1856:(NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of 6924:"Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study" 4647:

Zhu Q, Wani G, Wang QE, El-mahdy M, Snapka RM, Wani AA (July 2005). "Deubiquitination by proteasome is coordinated with substrate translocation for proteolysis in vivo".

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Although the proteasome normally produces very short peptide fragments, in some cases these products are themselves biologically active and functional molecules. Certain

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that decrease to normal levels in response to successful chemotherapy. Studies in animals have indicated that bortezomib may also have clinically significant effects in

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and necessarily occurs after deubiquitination. However, the order in which substrates are deubiquitinated and unfolded is not yet clear. Which of these processes is the

6142:"The cytoplasmic Hsp70 chaperone machinery subjects misfolded and endoplasmic reticulum import-incompetent proteins to degradation via the ubiquitin-proteasome system" 2537:

Löwe J, Stock D, Jap B, Zwickl P, Baumeister W, Huber R (April 1995). "Crystal structure of the 20S proteasome from the archaeon T. acidophilum at 3.4 A resolution".

1336:, the major protein component of Lewy bodies, under conditions of low proteasome activity. Impaired proteasomal activity may underlie cognitive disorders such as the 559:

The assembly of the proteasome is a complex process due to the number of subunits that must associate to form an active complex. The β subunits are synthesized with

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data revealing the stacked-ring structure of the proteasome became available in the mid-1980s, the first structure of the proteasome core particle was not solved by

696:(UBL) domain and one or more ubiquitin-associated (UBA) domains. The UBL domains are recognized by the 19S proteasome caps and the UBA domains bind ubiquitin via 5892:

Schwartz LM, Myer A, Kosz L, Engelstein M, Maier C (October 1990). "Activation of polyubiquitin gene expression during developmentally programmed cell death".

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Bashir T, Dorrello NV, Amador V, Guardavaccaro D, Pagano M (March 2004). "Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase".

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Chung KK, Dawson VL, Dawson TM (November 2001). "The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders".

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Murata S, Sasaki K, Kishimoto T, Niwa S, Hayashi H, Takahama Y, Tanaka K (June 2007). "Regulation of CD8+ T cell development by thymus-specific proteasomes".

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Kusmierczyk AR, Kunjappu MJ, Funakoshi M, Hochstrasser M (March 2008). "A multimeric assembly factor controls the formation of alternative 20S proteasomes".

700:. These receptor proteins may escort polyubiquitinated proteins to the proteasome, though the specifics of this interaction and its regulation are unclear. 8318: 1916: 356:

ring structures that are themselves composed of two different types of subunits; α subunits are structural in nature, whereas β subunits are predominantly

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Arrigo AP, Tanaka, K, Goldberg F, Welch WJ (1988). "Identity of 19S prosome particle with the large multifunctional protease complex of mammalian cells".

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been recently elucidated. 20S gate opening, and thus substrate degradation, requires the C-termini of the proteasomal ATPases, which contains a specific

92:. Once a protein is tagged with a single ubiquitin molecule, this is a signal to other ligases to attach additional ubiquitin molecules. The result is a 656:

Proteins are targeted for degradation by the proteasome with covalent modification of a lysine residue that requires the coordinated reactions of three

1732:. As part of the ubiquitin–proteasome system (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac 8206: 3247:

Lam YA, Lawson TG, Velayutham M, Zweier JL, Pickart CM (April 2002). "A proteasomal ATPase subunit recognizes the polyubiquitin degradation signal".

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The proteasomes form a pivotal component for the ubiquitin–proteasome system (UPS) and corresponding cellular Protein Quality Control (PQC). Protein

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proteins have been implicated in increasing the activity of the ubiquitin-proteasome system, though they are not direct participants in the process.

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segments of sufficient size, either at the protein terminus or internally, has also been proposed to facilitate efficient initiation of degradation.

173:. The importance of proteolytic degradation inside cells and the role of ubiquitin in proteolytic pathways was acknowledged in the award of the 2004 4164:

Fukunaga K, Kudo T, Toh-e A, Tanaka K, Saeki Y (June 2010). "Dissection of the assembly pathway of the proteasome lid in Saccharomyces cerevisiae".

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Dick TP, Nussbaum AK, Deeg M, Heinemeyer W, Groll M, Schirle M, Keilholz W, Stevanović S, Wolf DH, Huber R, Rammensee HG, Schild H (October 1998).

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regions, are degraded in a ubiquitin-independent manner. The most well-known example of a ubiquitin-independent proteasome substrate is the enzyme

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residue in concert with the adenylylation of a second ubiquitin. This adenylylated ubiquitin is then transferred to a cysteine of a second enzyme,

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to archaeal and eukaryotic β subunits, whereas the α sequence identity is much lower. The presence of 20S proteasomes in bacteria may result from

248:-dependent proteolytic complex that was responsible for ubiquitin-dependent protein degradation was discovered and was called the 26S proteasome. 150:

whose function is to maintain a "gate" through which proteins enter the barrel. These α subunits are controlled by binding to "cap" structures or

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Groll M, Ditzel L, Löwe J, Stock D, Bochtler M, Bartunik HD, Huber R (April 1997). "Structure of 20S proteasome from yeast at 2.4 A resolution".

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also promotes base assembly, but it is not essential. The lid assembles separately in a specific order and does not require assembly chaperones.

397:, the β1, β2, and β5 subunits are catalytic; although they share a common mechanism, they have three distinct substrate specificities considered 2502:

Kopp F, Steiner R, Dahlmann B, Kuehn L, Reinauer H (August 1986). "Size and shape of the multicatalytic proteinase from rat skeletal muscle".

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Ciehanover A, Hod Y, Hershko A (April 1978). "A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes".

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possess both the 20S and the hslV systems. Many bacteria also possess other homologs of the proteasome and an associated ATPase, most notably

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Seemüller E, Lupas A, Stock D, Löwe J, Huber R, Baumeister W (April 1995). "Proteasome from Thermoplasma acidophilum: a threonine protease".

3301:

Beck F, Unverdorben P, Bohn S, Schweitzer A, Pfeifer G, Sakata E, Nickell S, Plitzko JM, Villa E, Baumeister W, Förster F (September 2012).

213:-filled interiors that can degrade and then recycle exogenous proteins and aged or damaged organelles. However, work by Joseph Etlinger and 1622:

Proteasome inhibitors have also shown promise in treating autoimmune diseases in animal models. For example, studies in mice bearing human

1184:, or programmed cell death. The resulting deconstruction of cellular components is primarily carried out by specialized proteases known as 8361: 1437: 3767:"Structure of the 26S proteasome with ATP-γS bound provides insights into the mechanism of nucleotide-dependent substrate translocation" 3150:"ATP binding to PAN or the 26S ATPases causes association with the 20S proteasome, gate opening, and translocation of unfolded proteins" 2816:

Wilk S, Orlowski M (March 1983). "Evidence that pituitary cation-sensitive neutral endopeptidase is a multicatalytic protease complex".

2293:

Wilk S, Orlowski M (November 1980). "Cation-sensitive neutral endopeptidase: isolation and specificity of the bovine pituitary enzyme".

251:

Much of the early work leading up to the discovery of the ubiquitin proteasome system occurred in the late 1970s and early 1980s at the

5853:"Coordinated induction of the ubiquitin conjugation pathway accompanies the developmentally programmed death of insect skeletal muscle" 1324:, through mechanisms that are not yet well understood. Decreased proteasome activity has been suggested as a cause of aggregation and 1223:. The ability of proteasome inhibitors to induce apoptosis in rapidly dividing cells has been exploited in several recently developed 3924:"The axial channel of the proteasome core particle is gated by the Rpt2 ATPase and controls both substrate entry and product release" 3102:"An archaebacterial ATPase, homologous to ATPases in the eukaryotic 26 S proteasome, activates protein breakdown by 20 S proteasomes" 7329:

Sulistio YA, Heese K (January 2015). "The Ubiquitin–Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease".

6656: 1425:. Increased levels of proteasome activity correlate with disease activity and have been implicated in autoimmune diseases including 8407: 1372:. Although constitutively expressed proteasomes can participate in this process, a specialized complex composed of proteins, whose 775:

residues by the atomic structure of the substrate-engaged 26S proteasome in the deubiquitylation-compatible state, but substantial

577: 1615:-like activity is somewhat enhanced. Studies in animal models suggest that ritonavir may have inhibitory effects on the growth of 3578:

Schweitzer A, Aufderheide A, Rudack T, Beck F, Pfeifer G, Plitzko JM, Sakata E, Schulten K, Förster F, Baumeister W (July 2016).

921: 615: 294:, revealing mechanisms by which the substrate is recognized, deubiquitylated, unfolded and degraded by the human 26S proteasome. 1304:

Dysregulation of the ubiquitin proteasome system may contribute to several neural diseases. It may lead to brain tumors such as

4774:

van der Lee R, Lang B, Kruse K, Gsponer J, Sánchez de Groot N, Huynen MA, Matouschek A, Fuxreiter M, Babu MM (September 2014).

1785: 6189:

Dai Q, Qian SB, Li HH, McDonough H, Borchers C, Huang D, Takayama S, Younger JM, Ren HY, Cyr DM, Patterson C (November 2005).

5486:"Cyclin B dissociation from CDK1 precedes its degradation upon MPF inactivation in mitotic extracts of Xenopus laevis embryos" 8375: 7573:

Karin M, Delhase M (February 2000). "The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling".

3420:

Lasker K, Förster F, Bohn S, Walzthoeni T, Villa E, Unverdorben P, Beck F, Aebersold R, Sali A, Baumeister W (January 2012).

1968: 2747:"Docking of the proteasomal ATPases' carboxyl termini in the 20S proteasome's alpha ring opens the gate for substrate entry" 2659:

Wang J, Maldonado MA (August 2006). "The ubiquitin-proteasome system and its role in inflammatory and autoimmune diseases".

4823:

Smith DM, Benaroudj N, Goldberg A (October 2006). "Proteasomes and their associated ATPases: a destructive combination".

3646:"Structural mechanism for nucleotide-driven remodeling of the AAA-ATPase unfoldase in the activated human 26S proteasome" 925: 7099:"Proteasome inhibition reduces superantigen-mediated T cell activation and the severity of psoriasis in a SCID-hu model" 6804:"The proteasome inhibitor bortezomib enhances the activity of docetaxel in orthotopic human pancreatic tumor xenografts" 5118:

Voges D, Zwickl P, Baumeister W (1999). "The 26S proteasome: a molecular machine designed for controlled proteolysis".

2373:"ATP serves two distinct roles in protein degradation in reticulocytes, one requiring and one independent of ubiquitin" 8346: 7048:

Laurent N, de Boüard S, Guillamo JS, Christov C, Zini R, Jouault H, Andre P, Lotteau V, Peschanski M (February 2004).

1700:

Research has implicated UPS defects in the pathogenesis of neurodegenerative and myodegenerative disorders, including

8913: 8587: 1600: 784: 4909:"Repeat sequence of Epstein–Barr virus-encoded nuclear antigen 1 protein interrupts proteasome substrate processing" 4289:

Risseeuw EP, Daskalchuk TE, Banks TW, Liu E, Cotelesage J, Hellmann H, Estelle M, Somers DE, Crosby WL (June 2003).

1986:"Distinct 19 S and 20 S subcomplexes of the 26 S proteasome and their distribution in the nucleus and the cytoplasm" 727:

demands on these genes to produce enough ubiquitin for the cell. It has been proposed that ubiquitin is the slowest-

470:(hence called PCI subunits) assemble to a horseshoe-like structure enclosing the Rpn8/Rpn11 heterodimer. Rpn11, the 271:

provided key conceptual insights, though Rose later downplayed his role in the discovery. The three shared the 2004

197:

Before the discovery of the ubiquitin–proteasome system, protein degradation in cells was thought to rely mainly on

8603: 1584:. Preclinical and early clinical studies have been started to examine bortezomib's effectiveness in treating other 1361: 541: 3965:"The 1.9 A structure of a proteasome-11S activator complex and implications for proteasome-PAN/PA700 interactions" 2101:"A soluble ATP-dependent proteolytic system responsible for the degradation of abnormal proteins in reticulocytes" 924:

into p50 via internal proteolysis is one major example. Some proteins that are hypothesized to be unstable due to

551:(human). It opens only one α subunit in the 20S gate and itself folds into a dome with a very small pore over it. 8982: 8435: 564: 4682:

Wenzel T, Baumeister W (March 1995). "Conformational constraints in protein degradation by the 20S proteasome".

845:. The α subunits are represented as green spheres and the β subunits as protein backbones colored by individual 5527:"Mitotic checkpoint slippage in humans occurs via cyclin B destruction in the presence of an active checkpoint" 467: 4500:

Xu P, Duong DM, Seyfried NT, Cheng D, Xie Y, Robert J, Rush J, Hochstrasser M, Finley D, Peng J (April 2009).

4123:

Sakata E, Stengel F, Fukunaga K, Zhou M, Saeki Y, Förster F, Baumeister W, Tanaka K, Robinson CV (June 2011).

9084: 5079:"Contribution of proteasomal beta-subunits to the cleavage of peptide substrates analyzed with yeast mutants" 1721: 1713: 1261:

that identify misfolded or unfolded proteins and target them for proteasomal degradation are expressed. Both

796: 291: 5802:

Weijers D, Benkova E, Jäger KE, Schlereth A, Hamann T, Kientz M, Wilmoth JC, Reed JW, Jürgens G (May 2005).

4502:"Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation" 1607:

infection. However, it has been shown to inhibit proteasomes as well as free proteases; to be specific, the

8906: 8580: 8400: 7960:

Predmore JM, Wang P, Davis F, Bartolone S, Westfall MV, Dyke DB, Pagani F, Powell SR, Day SM (March 2010).

3708:"Deep classification of a large cryo-EM dataset defines the conformational landscape of the 26S proteasome" 3706:

Unverdorben P, Beck F, Śledź P, Schweitzer A, Pfeifer G, Plitzko JM, Baumeister W, Förster F (April 2014).

1865: 1426: 876:. The mechanism of proteolysis by the β subunits of the 20S core particle is through a threonine-dependent 673: 96:

that is bound by the proteasome, allowing it to degrade the tagged protein. The degradation process yields

8572: 7007:

Schmidtke G, Holzhütter HG, Bogyo M, Kairies N, Groll M, de Giuli R, Emch S, Groettrup M (December 1999).

4330:

Elsasser S, Finley D (August 2005). "Delivery of ubiquitinated substrates to protein-unfolding machines".

2917:"The active sites of the eukaryotic 20 S proteasome and their involvement in subunit precursor processing" 1576:. Notably, multiple myeloma has been observed to result in increased proteasome-derived peptide levels in 1289:

proteins via the proteasome system. In particular, proteasomes localized to the nucleus are regulated by

1135:

Like eukaryotes, some archaea also use the proteasome to control cell cycle, specifically by controlling

661: 2195:"Isopeptide linkage between nonhistone and histone 2A polypeptides of chromosomal conjugate-protein A24" 1661:

inhibitors have also been developed to specifically label the active sites of the assembled proteasome.

830:

gene products bearing this sequence can stall the proteasome, helping the virus propagate by preventing

319:). The proteasome most exclusively used in mammals is the cytosolic 26S proteasome, which is about 2000 9342: 6679:"Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma" 2863: 2603:

Dong Y, Zhang S, Wu Z, Li X, Wang WL, Zhu Y, Stoilova-McPhie S, Lu Y, Finley D, Mao Y (November 2018).

1777: 1565: 1547: 1290: 1086: 8214:"Early work on the ubiquitin proteasome system, an interview with Aaron Ciechanover. Interview by CDD" 7474:"Targeting the ubiquitin–proteasome system in heart disease: the basis for new therapeutic strategies" 5277:"Determinants of proteasome recognition of ornithine decarboxylase, a ubiquitin-independent substrate" 2254:"Early work on the ubiquitin proteasome system, an interview with Aaron Ciechanover. Interview by CDD" 6720:"Circulating proteasome levels are an independent prognostic factor for survival in multiple myeloma" 3198:

Liu CW, Li X, Thompson D, Wooding K, Chang TL, Tang Z, Yu H, Thomas PJ, DeMartino GN (October 2006).

1589: 454:

In 2012, two independent efforts have elucidated the molecular architecture of the 26S proteasome by

5804:"Developmental specificity of auxin response by pairs of ARF and Aux/IAA transcriptional regulators" 5668:"The oncoprotein gankyrin negatively regulates both p53 and RB by enhancing proteasomal degradation" 9079: 8607: 6922:

Messinger YH, Gaynon PS, Sposto R, van der Giessen J, Eckroth E, Malvar J, Bostrom BC (July 2012).

3476:

Chen S, Wu J, Lu Y, Ma YB, Lee BH, Yu Z, Ouyang Q, Finley DJ, Kirschner MW, Mao Y (November 2016).

1906: 1337: 1129: 1047: 724: 681: 455: 272: 174: 8249:"Early work on the ubiquitin proteasome system, an interview with Avram Hershko. Interview by CDD" 6497:"26S proteasomes and immunoproteasomes produce mainly N-extended versions of an antigenic peptide" 5240:

Asher G, Reuven N, Shaul Y (August 2006). "20S proteasomes and protein degradation "by default"".

4414:

Sharp PM, Li WH (1987). "Ubiquitin genes as a paradigm of concerted evolution of tandem repeats".

4004:

Witt S, Kwon YD, Sharon M, Felderer K, Beuttler M, Robinson CV, Baumeister W, Jap BK (July 2006).

3535:

Huang X, Luan B, Wu J, Shi Y (September 2016). "An atomic structure of the human 26S proteasome".

2463:"Early work on the ubiquitin proteasome system, an interview with Avram Hershko. Interview by CDD" 609:

subunits and their main function seems to be to ensure proper assembly of the heterohexameric AAA-

389:, all the α and all the β subunits are identical, whereas eukaryotic proteasomes such as those in 8393: 7190:"A fluorescent broad-spectrum proteasome inhibitor for labeling proteasomes in vitro and in vivo" 1857: 1737: 1717: 1365: 1341: 1254: 1109: 1027: 929: 867: 712: 471: 268: 4991:

Coux O, Tanaka K, Goldberg AL (1996). "Structure and functions of the 20S and 26S proteasomes".

4080:

Murata S, Yashiroda H, Tanaka K (February 2009). "Molecular mechanisms of proteasome assembly".

3422:"Molecular architecture of the 26S proteasome holocomplex determined by an integrative approach" 1876:(RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers. 1368:. These peptides are products of proteasomal degradation of proteins originated by the invading 9044: 9019: 8284:"Early work on the ubiquitin proteasome system, an interview with Irwin Rose. Interview by CDD" 5759:

Dharmasiri S, Estelle M (2002). "The role of regulated protein degradation in auxin response".

3873:

Lu Y, Wu J, Dong Y, Chen S, Sun S, Ma YB, Ouyang Q, Finley D, Kirschner MW, Mao Y (July 2017).

3765:Śledź P, Unverdorben P, Beck F, Pfeifer G, Schweitzer A, Förster F, Baumeister W (April 2013). 3010:"Plasticity in eucaryotic 20S proteasome ring assembly revealed by a subunit deletion in yeast" 2421: 2078: 1947:

Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J (2004).

1705: 1701: 1551: 1317: 1313: 917: 827: 693: 484: 245: 8009:

Powell SR (July 2006). "The ubiquitin-proteasome system in cardiac physiology and pathology".

5370:"Ubiquitin conjugation is not required for the degradation of oxidized proteins by proteasome" 1641:

Labeling and inhibition of the proteasome is also of interest in laboratory settings for both

1386:. Another β5i variant subunit, β5t, is expressed in the thymus, leading to a thymus-specific " 895:

regulating the expression of specific genes, including one component of the mammalian complex

9283: 9069: 8962: 8539: 4776:"Intrinsically disordered segments affect protein half-life in the cell and during evolution" 1960: 1954: 1745: 1011: 800: 536: 283: 8319:"Targeting of nuclear factor-kappaB and proteasome by dithiocarbamate complexes with metals" 8087:

Ben-Neriah Y (January 2002). "Regulatory functions of ubiquitination in the immune system".

7876:

Mayer RJ (March 2003). "From neurodegeneration to neurohomeostasis: the role of ubiquitin".

491: 161:

The proteasomal degradation pathway is essential for many cellular processes, including the

9316: 8430: 6612: 6557: 6546:"Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21)" 6453: 5035: 4957: 4603: 4423: 4125:"The catalytic activity of Ubp6 enhances maturation of the proteasomal regulatory particle" 3778: 3719: 3657: 3591: 3489: 3376: 3314: 3256: 2546: 2206: 2112: 1873: 1725: 1516: 1457: 1430: 1205: 1164: 892: 831: 519: 105: 6851:

Schenkein D (June 2002). "Proteasome inhibitors in the treatment of B-cell malignancies".

4465:

Pickart CM, Fushman D (December 2004). "Polyubiquitin chains: polymeric protein signals".

576:

of the propeptides to expose the active site. These β interactions are mediated mainly by

8: 9347: 8942: 7657:

Checler F, da Costa CA, Ancolio K, Chevallier N, Lopez-Perez E, Marambaud P (July 2000).

6653: 6140:

Park SH, Bolender N, Eisele F, Kostova Z, Takeuchi J, Coffino P, Wolf DH (January 2007).

2794: 1901: 1649:

study of proteasomal activity in cells. The most commonly used laboratory inhibitors are

1393:

The strength of MHC class I ligand binding is dependent on the composition of the ligand

1270: 900: 715:

sequence and is found in all known eukaryotic organisms. The genes encoding ubiquitin in

598: 573: 523: 279: 8052:

Adams J (April 2003). "Potential for proteasome inhibition in the treatment of cancer".

6616: 6561: 6457: 5039: 5004: 4961: 4607: 4427: 3782: 3723: 3661: 3595: 3493: 3380: 3318: 3260: 2550: 2210: 2116: 1869: 9352: 8112: 8034: 7986: 7961: 7937: 7912: 7858: 7815: 7772: 7726: 7634: 7609: 7547: 7522: 7498: 7473: 7449: 7424: 7400: 7373: 7354: 7265: 7240: 7079: 6989: 6833: 6784: 6636: 6580: 6545: 6477: 6426: 6378: 6361: 6337: 6312: 6255: 6166: 6141: 6009: 5966: 5917: 5828: 5803: 5784: 5736: 5709: 5648: 5600: 5575: 5551: 5526: 5181: 5059: 4884: 4859: 4800: 4775: 4751: 4726: 4707: 4624: 4591: 4526: 4501: 4447: 4355: 4266: 4241: 4105: 3899: 3874: 3850: 3825: 3801: 3766: 3742: 3707: 3678: 3645: 3614: 3579: 3560: 3512: 3477: 3448: 3421: 3397: 3364: 3337: 3302: 3280: 3224: 3199: 3082: 3034: 3009: 2985: 2961:"Assembly of an Evolutionarily Conserved Alternative Proteasome Isoform in Human Cells" 2960: 2894: 2841: 2829: 2771: 2746: 2717: 2692: 2629: 2604: 2397: 2372: 2361: 2318: 2306: 2056: 1861: 1833: 1773: 1555: 1422: 1258: 1059: 968: 776: 771: 214: 104:

long, which can then be further degraded into shorter amino acid sequences and used in

8898: 8190: 8163: 8065: 7977: 7714: 7675: 7658: 7164: 7147: 7123: 7098: 6521: 6496: 6286: 5953: 5936: 5427: 5301: 5276: 5131: 4565: 4217: 4200: 4058: 3940: 3923: 3200:"ATP binding and ATP hydrolysis play distinct roles in the function of 26S proteasome" 2438: 2229: 2194: 2135: 2100: 2002: 1985: 1630:

after treatment with a proteasome inhibitor. Inhibitors also show positive effects in

1568:

and marketed as Velcade, is the first proteasome inhibitor to reach clinical use as a

9337: 9266: 9104: 8987: 8471: 8445: 8338: 8305: 8270: 8235: 8195: 8140: 8104: 8069: 8026: 7991: 7962:"Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies" 7942: 7893: 7850: 7807: 7803: 7764: 7718: 7680: 7639: 7590: 7552: 7503: 7454: 7405: 7346: 7311: 7306: 7289: 7270: 7221: 7169: 7128: 7071: 7050:"Effects of the proteasome inhibitor ritonavir on glioma growth in vitro and in vivo" 7030: 6981: 6945: 6904: 6868: 6825: 6776: 6741: 6700: 6628: 6585: 6526: 6469: 6418: 6383: 6342: 6290: 6247: 6212: 6171: 6122: 6081: 6040: 6001: 5997: 5958: 5909: 5905: 5874: 5833: 5776: 5741: 5689: 5640: 5605: 5556: 5507: 5466: 5462: 5431: 5391: 5347: 5306: 5257: 5222: 5173: 5135: 5100: 5051: 5008: 4973: 4930: 4889: 4840: 4805: 4756: 4699: 4664: 4629: 4569: 4531: 4482: 4439: 4396: 4391: 4374: 4347: 4312: 4307: 4290: 4271: 4222: 4181: 4146: 4097: 4062: 4027: 3986: 3945: 3904: 3855: 3806: 3747: 3683: 3619: 3552: 3517: 3453: 3402: 3342: 3272: 3229: 3171: 3123: 3074: 3039: 2990: 2938: 2886: 2833: 2776: 2722: 2668: 2634: 2562: 2519: 2515: 2484: 2443: 2422:"Purification of two high molecular weight proteases from rabbit reticulocyte lysate" 2402: 2353: 2310: 2275: 2234: 2175: 2171: 2140: 2048: 2007: 1964: 1949: 1709: 1581: 1353: 1309: 1233: 1066: 1007: 1000: 846: 841:

A cutaway view of the proteasome 20S core particle illustrating the locations of the

811: 260: 178: 135: 54: 8116: 7819: 7776: 7358: 7083: 6993: 6837: 6788: 6640: 6544:

Mallery DL, McEwan WA, Bidgood SR, Towers GJ, Johnson CM, James LC (November 2010).

6481: 6430: 6259: 6101:"Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties" 6013: 5970: 5921: 4711: 4359: 4109: 3564: 3363:

Lander GC, Estrin E, Matyskiela ME, Bashore C, Nogales E, Martin A (February 2012).

3086: 2898: 2845: 2060: 1681:

and degradation by the proteasome are important mechanisms in the regulation of the

1508:= yellow), surrounded by the local protein surface. The blue patch is the catalytic 651: 369: 336:

role in degradation of foreign peptides such as those produced after infection by a

8549: 8507: 8502: 8497: 8330: 8295: 8260: 8225: 8185: 8175: 8096: 8061: 8038: 8018: 7981: 7973: 7932: 7924: 7885: 7862: 7842: 7799: 7756: 7730: 7710: 7670: 7629: 7621: 7582: 7542: 7534: 7493: 7485: 7444: 7436: 7395: 7385: 7338: 7301: 7260: 7252: 7211: 7206: 7201: 7189: 7159: 7118: 7110: 7061: 7020: 6973: 6935: 6896: 6860: 6815: 6768: 6731: 6690: 6620: 6575: 6565: 6516: 6508: 6461: 6410: 6373: 6332: 6324: 6282: 6239: 6202: 6191:"Regulation of the cytoplasmic quality control protein degradation pathway by BAG2" 6161: 6153: 6112: 6071: 5993: 5948: 5901: 5864: 5823: 5815: 5788: 5768: 5731: 5721: 5679: 5652: 5632: 5595: 5587: 5546: 5538: 5497: 5458: 5423: 5381: 5337: 5296: 5288: 5249: 5212: 5201:"Productive RUPture: activation of transcription factors by proteasomal processing" 5185: 5165: 5127: 5090: 5063: 5043: 5000: 4965: 4920: 4879: 4871: 4832: 4795: 4787: 4746: 4738: 4691: 4656: 4619: 4611: 4561: 4521: 4513: 4474: 4451: 4431: 4386: 4339: 4302: 4291:"Protein interaction analysis of SCF ubiquitin E3 ligase subunits from Arabidopsis" 4261: 4253: 4212: 4173: 4136: 4089: 4054: 4017: 3976: 3935: 3894: 3886: 3845: 3837: 3796: 3786: 3737: 3727: 3673: 3665: 3609: 3599: 3544: 3507: 3497: 3443: 3433: 3392: 3384: 3332: 3322: 3284: 3264: 3219: 3211: 3161: 3113: 3066: 3029: 3021: 2980: 2972: 2928: 2878: 2825: 2766: 2758: 2712: 2704: 2624: 2616: 2554: 2511: 2474: 2433: 2392: 2384: 2345: 2322: 2302: 2265: 2224: 2214: 2167: 2130: 2120: 2038: 1997: 1573: 1475: 1445: 1382: 1377: 1312:

diseases that share aggregation of misfolded proteins as a common feature, such as

1090: 1015: 975:

The 20S proteasome is both ubiquitous and essential in eukaryotes and archaea. The

963: 807: 677: 641:

that serves as a molecular tag targeting proteins for degradation by the proteasome

463: 430: 425: 320: 170: 89: 8372: 6664: 5576:"Regulation of late G1/S phase transition and APC Cdh1 by reactive oxygen species" 4201:"Ubiquitin-activating enzyme. Mechanism and role in protein-ubiquitin conjugation" 1196:

of pro-growth cell cycle proteins. However, some cell lines — in particular,

263:

worked as a graduate student. Hershko's year-long sabbatical in the laboratory of

8967: 8455: 8440: 8379: 8180: 7889: 6940: 6923: 6736: 6719: 6660: 6099:

Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G (November 2006).

5217: 5200: 4791: 4141: 4124: 3981: 3964: 3890: 3215: 3166: 3149: 2976: 2762: 2708: 2365: 1911: 1789: 1387: 1373: 1333: 1197: 1014:, while the diversification of subunits among eukaryotes is ascribed to multiple 980: 547:

Yet another type of non-ATPase regulatory particle is the Blm10 (yeast) or PA200/

166: 81: 42: 9126: 8022: 7928: 7440: 7290:"New insights into proteasome function: from archaebacteria to drug development" 4660: 3875:"Conformational Landscape of the p28-Bound Human Proteasome Regulatory Particle" 2504:

Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology

1352:

The proteasome plays a straightforward but critical role in the function of the

8930: 8476: 8334: 7538: 7097:

Zollner TM, Podda M, Pien C, Elliott PJ, Kaufmann R, Boehncke WH (March 2002).

6550: