Proteasome

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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 degraded.
Top view of the proteasome above.

Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.

Proteasomes are part of a major mechanism by which cells regulate the concentration of particular proteins and degrade misfolded proteins. Proteins are tagged for degradation with a small protein called ubiquitin. The tagging reaction is catalyzed by enzymes called ubiquitin ligases. 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 polyubiquitin chain that is bound by the proteasome, allowing it to degrade the tagged protein.[1] The degradation process yields peptides of about seven to eight amino acids long, which can then be further degraded into shorter amino acid sequences and used in synthesizing new proteins.[1]

Proteasomes are found inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, proteasomes are located both in the nucleus and in the cytoplasm.[2]

In structure, 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 β subunits that contain three to seven protease active sites. 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 α subunits whose function is to maintain a "gate" through which proteins enter the barrel. These α subunits are controlled by binding to "cap" structures or regulatory particles 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 ubiquitin–proteasome system.[3]

The proteasomal degradation pathway is essential for many cellular processes, including the cell cycle, the regulation of gene expression, and responses to oxidative stress. The importance of proteolytic degradation inside cells and the role of ubiquitin in proteolytic pathways was acknowledged in the award of the 2004 Nobel Prize in Chemistry to Aaron Ciechanover, Avram Hershko and Irwin Rose.[4]

Discovery

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

covalent modification of the histone protein by a bond between a lysine side chain of the histone and the C-terminal glycine residue of ubiquitin, a protein that had no known function.[7] 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.[8] 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.[9] Later, the ATP-dependent proteolytic complex that was responsible for ubiquitin-dependent protein degradation was discovered and was called the 26S proteasome.[10][11]

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

Technion in the laboratory of Avram Hershko, where Aaron Ciechanover worked as a graduate student. Hershko's year-long sabbatical in the laboratory of Irwin Rose at the Fox Chase Cancer Center provided key conceptual insights, though Rose later downplayed his role in the discovery.[12] The three shared the 2004 Nobel Prize in Chemistry for their work in discovering this system.[4]

Although

electron microscopy data revealing the stacked-ring structure of the proteasome became available in the mid-1980s,[13] the first structure of the proteasome core particle was not solved by X-ray crystallography until 1994.[14] In 2018, the first atomic structures of the human 26S proteasome holoenzyme in complex with a polyubiquitylated protein substrate were solved by cryogenic electron microscopy, revealing mechanisms by which the substrate is recognized, deubiquitylated, unfolded and degraded by the human 26S proteasome.[15]

Structure and organization

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 blue.

The proteasome subcomponents are often referred to by their

kilodaltons (kDa) in molecular mass 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 that contains multiple ATPase active sites and ubiquitin binding sites; it is this structure that recognizes polyubiquitinated proteins and transfers them to the catalytic core.[15] 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 role in degradation of foreign peptides such as those produced after infection by a virus.[16]

20S core particle

"20S" redirects here. For the decade, see 20s.

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 ring structures that are themselves composed of two different types of subunits; α subunits are structural in nature, whereas β subunits are predominantly catalytic. The α subunits are pseudoenzymes homologous to β subunits. They are assembled with their N-termini adjacent to that of the β subunits.[17] 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 (Pfam PF10584) form a gate that blocks unregulated access of substrates to the interior cavity.[18] 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.[19] Three distinct catalytic activities were identified in the purified complex: chymotrypsin-like, trypsin-like and peptidylglutamyl-peptide hydrolyzing.[20] The size of the proteasome is relatively conserved and is about 150 angstroms (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.[21]

In

hematopoietic cells in response to exposure to pro-inflammatory signals such as cytokines, in particular, interferon gamma. The proteasome assembled with these alternative subunits is known as the immunoproteasome, whose substrate specificity is altered relative to the normal proteasome.[21]
Recently an alternative proteasome was identified in human cells that lack the α3 core subunit.[23] 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.[24] 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.[23][25]

19S regulatory particle

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 homolog of these ATPases exists in archaea, called PAN (proteasome-activating nucleotidase).[26] 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).[27][28] 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.[28][29]

Cartoon representation of the 26S proteasome.[30]

In 2012, two independent efforts have elucidated the molecular architecture of the 26S proteasome by single particle electron microscopy.[31][32] 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.[33][34][35] 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.[15] In the heart of the 19S, directly adjacent to the 20S, are the AAA-ATPases (AAA proteins) 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 COP9 complex and eIF3 (hence called PCI subunits) assemble to a horseshoe-like structure enclosing the Rpn8/Rpn11 heterodimer. Rpn11, the deubiquitinating enzyme, 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.

Conformational changes of 19S

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.[36][37] A hallmark of the AAA-ATPase configuration in this predominant low-energy state is a staircase- or lockwasher-like arrangement of the AAA-domains.[30][31] In the presence of ATP 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.[33][37] In the presence of ATP-γS or a substrate, considerably more conformations have been observed displaying dramatic structural changes of the AAA-ATPase module.[15][36][38][39] 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.[15][36] Prior to the 26S assembly, the 19S regulatory particle in a free form has also been observed in seven conformational states.[40] 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.

Three distinct conformational states of the 26S proteasome.[37] 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 occurs.

Regulation of the 20S by the 19S

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.[41] The mechanism by which the proteasomal ATPase open this gate has been recently elucidated.[18] 20S gate opening, and thus substrate degradation, requires the C-termini of the proteasomal ATPases, which contains a specific motif (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.[18] 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.[36][15][33]

Other regulatory particles

"11S" redirects here. Not to be confused with S11 or 11 (plural).

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 peptides 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.[17] The mechanisms by which it binds to the core particle through the C-terminal tails of its subunits and induces α-ring conformational changes to open the 20S gate suggest a similar mechanism for the 19S particle.[42] 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 major histocompatibility complex.[16]

Yet another type of non-ATPase regulatory particle is the Blm10 (yeast) or PA200/PSME4 (human). It opens only one α subunit in the 20S gate and itself folds into a dome with a very small pore over it.[17]

Assembly

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

hydrophobic interactions between conserved alpha helices whose disruption by mutation damages the proteasome's ability to assemble.[43] 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.[44]

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

gankyrin (names for yeast/mammals).[45] These assembly chaperones bind to the AAA-ATPase subunits and their main function seems to be to ensure proper assembly of the heterohexameric AAA-ATPase 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 Ubp6/Usp14 also promotes base assembly, but it is not essential.[46] The lid assembles separately in a specific order and does not require assembly chaperones.[47]

Protein degradation process

Ribbon diagram of ubiquitin, the highly conserved protein that serves as a molecular tag targeting proteins for degradation by the proteasome

Ubiquitination and targeting

Further information: Ubiquitin § Ubiquitination

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

substrate specificity to this system.[50]
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.

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 targeting and engagement.

N-terminal ubiquitin-like (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 three-helix bundles. These receptor proteins may escort polyubiquitinated proteins to the proteasome, though the specifics of this interaction and its regulation are unclear.[51]

The

transcription demands on these genes to produce enough ubiquitin for the cell. It has been proposed that ubiquitin is the slowest-evolving protein identified to date.[53] Ubiquitin contains seven lysine residues to which another ubiquitin can be ligated, resulting in different types of polyubiquitin chains.[54] Chains in which each additional ubiquitin is linked to lysine 48 of the previous ubiquitin have a role in proteasome targeting, while other types of chains may be involved in other processes.[55][56]

The ubiquitination pathway

Deubiquitylation

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 in cells.[56] 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 EB.[15] 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. [57] 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.[57] These observations imply that the proteasome regulation may depend on its dynamic transitions of conformational states.

Unfolding and translocation

After a protein has been ubiquitinated, it is recognized by the 19S regulatory particle in an ATP-dependent binding step.

disulfide bonds, are sufficient to inhibit degradation.[59] The presence of intrinsically disordered protein segments of sufficient size, either at the protein terminus or internally, has also been proposed to facilitate efficient initiation of degradation.[60][61]

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 hydrolyzed before translocation. While energy is needed for substrate unfolding, it is not required for translocation.[27][28] The assembled 26S proteasome can degrade unfolded proteins in the presence of a non-hydrolyzable ATP analog, but cannot degrade folded proteins, indicating that energy from ATP hydrolysis is used for substrate unfolding.[27] Passage of the unfolded substrate through the opened gate occurs via facilitated diffusion if the 19S cap is in the ATP-bound state.[62]

The mechanism for unfolding of

amino acid sequence. Long sequences of alternating glycine and alanine 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.[63] Such glycine-alanine repeats are also found in nature, for example in silk fibroin; in particular, certain Epstein–Barr virus gene products bearing this sequence can stall the proteasome, helping the virus propagate by preventing antigen presentation on the major histocompatibility complex.[64]

polypeptide chain. The small pink spheres represent the location of the active-site threonine residue in each subunit. Light blue chemical structures are the inhibitor bortezomib
bound to the active sites.

Proteolysis

See also: threonine protease § mechanism

The proteasome functions as an

hydroxyl. 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.[69] 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.[22]

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

loops on these proteins' surfaces serve as the proteasomal substrates and enter the central cavity, while the majority of the protein remains outside.[70] Similar effects have been observed in yeast proteins; this mechanism of selective degradation is known as regulated ubiquitin/proteasome dependent processing (RUP).[71]

Ubiquitin-independent degradation

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-

intrinsically unstructured regions,[72] are degraded in a ubiquitin-independent manner. The most well-known example of a ubiquitin-independent proteasome substrate is the enzyme ornithine decarboxylase.[73] Ubiquitin-independent mechanisms targeting key cell cycle regulators such as p53 have also been reported, although p53 is also subject to ubiquitin-dependent degradation.[74] Finally, structurally abnormal, misfolded, or highly oxidized proteins are also subject to ubiquitin-independent and 19S-independent degradation under conditions of cellular stress.[75]

Evolution

hslU (red) from E. coli. This complex of heat shock proteins
is thought to resemble the ancestor of the modern proteasome.

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

hslU, whose gene products are a multimeric protease arranged in a two-layered ring and an ATPase.[76] The hslV protein has been hypothesized to resemble the likely ancestor of the 20S proteasome.[77] In general, HslV is not essential in bacteria, and not all bacteria possess it, whereas some protists possess both the 20S and the hslV systems.[76] Many bacteria also possess other homologs of the proteasome and an associated ATPase, most notably ClpP and ClpX
. This redundancy explains why the HslUV system is not essential.

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

lateral gene transfer, while the diversification of subunits among eukaryotes is ascribed to multiple gene duplication events.[76]

Cell cycle control

Cell cycle progression is controlled by ordered action of

M phase exit can occur despite the delay of this exit by the spindle checkpoint.[79]

Earlier cell cycle checkpoints such as post-

anaphase promoting complex (APC), an E3 ubiquitin ligase.[80] The APC and the Skp1/Cul1/F-box protein complex (SCF complex) 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.[81]

Individual components of the 19S particle have their own regulatory roles.

tumor cell types such as hepatocellular carcinoma.[82]

Like eukaryotes, some archaea also use the proteasome to control cell cycle, specifically by controlling ESCRT-III-mediated cell division.[83]

Regulation of plant growth

In

phytohormones that order the direction and tropism of plant growth, induces the targeting of a class of transcription factor 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 expression.[84] 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.[85]

Apoptosis

Both internal and external

blebs characteristic of apoptosis.[89]

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 of pro-growth cell cycle proteins.

JNK.[91] The ability of proteasome inhibitors to induce apoptosis in rapidly dividing cells has been exploited in several recently developed chemotherapy agents such as bortezomib and salinosporamide A
.

Response to cellular stress

In response to cellular stresses – such as

hydrophobic patches on the surface of misfolded proteins and recruits E3 ubiquitin ligases such as CHIP to tag the proteins for proteasomal degradation.[93] The CHIP protein (carboxyl terminus of Hsp70-interacting protein) is itself regulated via inhibition of interactions between the E3 enzyme CHIP and its E2 binding partner.[94]

Similar mechanisms exist to promote the degradation of

aging.[96]

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

inclusion body myopathy.[97]

Role in the immune system

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

adaptive immune system. Peptide antigens are displayed by the major histocompatibility complex class I (MHC) proteins on the surface of antigen-presenting cells. These peptides are products of proteasomal degradation of proteins originated by the invading pathogen. Although constitutively expressed proteasomes can participate in this process, a specialized complex composed of proteins, whose expression is induced by interferon gamma, 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 immunoproteasome.[16] Another β5i variant subunit, β5t, is expressed in the thymus, leading to a thymus-specific "thymoproteasome" whose function is as yet unclear.[100]

The strength of MHC class I ligand binding is dependent on the composition of the ligand C-terminus, as peptides bind by hydrogen bonding 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.[101]

Due to its role in generating the activated form of

systemic lupus erythematosus and rheumatoid arthritis.[16]

The proteasome is also involved in

Intracellular antibody-mediated proteolysis of antibody-bound virions. In this neutralisation pathway, TRIM21 (a protein of the tripartite motif family) binds with immunoglobulin G to direct the virion to the proteasome where it is degraded.[102]

Proteasome inhibitors

Main article: Proteasome inhibitor
Chemical structure of bortezomib (Boronated form of MG132), a proteasome inhibitor used in chemotherapy that is particularly effective against multiple myeloma
Bortezomib bound to the core particle in a yeast proteasome. The bortezomib molecule is in the center colored by atom type (carbon = pink, nitrogen = blue, oxygen = red, boron = yellow), surrounded by the local protein surface. The blue patch is the catalytic threonine residue whose activity is blocked by the presence of bortezomib.

tumor activity in cell culture, inducing apoptosis by disrupting the regulated degradation of pro-growth cell cycle proteins.[90]
This approach of selectively inducing apoptosis in tumor cells has proven effective in animal models and human trials.

Takeda Pharmaceuticals. 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 threonine protease
.

non-Hodgkin's lymphoma.[110] Clinical results also seem to justify use of proteasome inhibitor combined with chemotherapy, for B-cell acute lymphoblastic leukemia [111] Proteasome inhibitors can kill some types of cultured leukemia cells that are resistant to glucocorticoids.[112]

The molecule ritonavir, marketed as Norvir, was developed as a protease inhibitor and used to target HIV infection. However, it has been shown to inhibit proteasomes as well as free proteases; to be specific, the chymotrypsin-like activity of the proteasome is inhibited by ritonavir, while the trypsin-like activity is somewhat enhanced.[113] Studies in animal models suggest that ritonavir may have inhibitory effects on the growth of glioma cells.[114]

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

skin grafts found a reduction in the size of lesions from psoriasis after treatment with a proteasome inhibitor.[115] Inhibitors also show positive effects in rodent models of asthma.[116]

Labeling and inhibition of the proteasome is also of interest in laboratory settings for both in vitro and in vivo study of proteasomal activity in cells. The most commonly used laboratory inhibitors are

Fluorescent inhibitors have also been developed to specifically label the active sites of the assembled proteasome.[117]

Clinical significance

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 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.

The proteasomes form a pivotal component for the ubiquitin–proteasome system (UPS)

malignancies.[126]

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

SLE, Sjögren syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[138]

See also

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  58. PMID 15950624
    .
  59. S2CID 41599619
    .
  60. PMID 21278740
    .
  61. PMID 25220455
    .
  62. PMID 16919475
    .
  63. PMID 16601692
    .
  64. PMID 14688254
    .
  65. PMID 7725107
    .
  66. PMID 8811196
    .
  67. S2CID 4261663
    .
  68. PMID 9748229
    .
  69. PMID 10872471
    .
  70. ^
    S2CID 7126477
    .
  71. PMID 15571816
    .
  72. PMID 16927316
    .
  73. PMID 12660156
    .
  74. PMID 16082197
    .
  75. ^
    PMID 12401807
    .
  76. ^
    PMID 12595256
    .
  77. PMID 10410804
    .
  78. PMID 16921258
    .
  79. PMID 16782009
    .
  80. PMID 16738333
    .
  81. S2CID 4401971
    .
  82. PMID 16177571
    .
  83. PMID 32764038
    .
  84. S2CID 7669386
    .
  85. PMID 15889151
    .
  86. PMID 7721865
    .
  87. S2CID 33829749
    .
  88. S2CID 10873052
    .
  89. S2CID 29256092
    .
  90. ^
    PMID 10363983
    .
  91. PMID 10381632
    .
  92. PMID 17106261
    .
  93. PMID 17065559
    .
  94. PMID 16169850
    .
  95. S2CID 30385354
    .
  96. PMID 11295490
    .
  97. ^
    PMID 19597829
    .
  98. PMID 16717251
    .
  99. S2CID 27762513
    .
  100. S2CID 37185716
    .
  101. PMID 11350924
    .
  102. PMID 21045130
    .
  103. S2CID 37779687
    .
  104. ^ United States Food and Drug Administration press release Archived 19 February 2007 at the Wayback Machine 13 May 2003. Access date 29 December 2006. See also FDA Velcade information page.
  105. PMID 17001068
    .
  106. PMID 17095627
    .
  107. S2CID 21223980
    .
  108. S2CID 38429730
    .
  109. PMID 12141956
    .
  110. PMID 15613699
    .
  111. PMID 22653976
    .
  112. S2CID 28749125
    .
  113. PMID 10585454
    .
  114. S2CID 24423806
    .
  115. PMID 11877475
    .
  116. PMID 10452747
    .
  117. PMID 17114003
    .
  118. PMID 24457024
    .
  119. PMID 9383453
    .
  120. S2CID 14103185
    .
  121. PMID 25324717
    .
  122. PMID 24380730
    .
  123. PMID 25133688
    .
  124. PMID 25651176
    .
  125. ^
    PMID 10723801
    .
  126. PMID 25560147
    .
  127. PMID 10899438
    .
  128. ^
    S2CID 2211658
    .
  129. ^
    S2CID 22396490
    .
  130. S2CID 28190967
    .
  131. S2CID 5780576
    .
  132. PMID 12792671
    .
  133. PMID 23220331
    .
  134. PMID 20159828
    .
  135. S2CID 7073263
    .
  136. PMID 12654543
    .
  137. S2CID 26973319
    .
  138. PMID 12375310
    .

Further reading

External links

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