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• W1991930087 abstract "Protein degradation is a necessity for many reasons: Homeostasis must be maintained while cellular structures are continually rebuilt, in particular during development or in response to external stimuli. Proteins misfolded as a consequence of mutations or ensuing from heat or oxidative stress must be scavenged because they are prone to aggregation. Beyond these more mundane “housekeeping” functions, protein degradation provides a means to terminate the lifespan of many regulatory proteins at distinct times; amongst them are cyclins, transcription factors, and components of signal transduction pathways (for reviews, see19Coux O Tanaka K Goldberg A.L Structure and functions of the 20S and 26S proteasomes.Annu. Rev. Biochem. 1996; 65: 801-847Crossref PubMed Scopus (2144) Google Scholar, 48Hilt W Wolf D.H Proteasomes destruction as a programme.Trends Biochem. Sci. 1996; 21: 96-102Abstract Full Text PDF PubMed Scopus (357) Google Scholar, 96Varshavsky A The ubiquitin system.Trends Biochem. Sci. 1997; 22: 383-387Abstract Full Text PDF PubMed Scopus (495) Google Scholar). Moreover, the immune system relies on the availability of immunocompetent peptides generated by the degradation of foreign antigens (for reviews, see38Goldberg A.L Gaczynska M Grant E Michalek M Rock K.L Functions of the proteasome in antigen presentation.Cold Spring Harb. Symp. Quant. Biol. 1995; 60: 479-490Crossref PubMed Scopus (45) Google Scholar, 45Heemels M.T Ploegh H Generation, translocation, and presentation of MHC class I–restricted peptides.Annu Rev. Biochem. 1995; 64: 463-491Crossref PubMed Scopus (407) Google Scholar). However, since protein degradation is also a hazard, it must be subject to spatial and temporal control in order to prevent the destruction of proteins not destined for degradation. A basic stratagem in controlling protein degradation is compartmentalization, that is, the confinement of the proteolytic action to sites that can only be accessed by proteins displaying some sort of degradation signal. Such a compartment can be an organelle delimited by a membrane, as in the case of the lysosome. Proteins to be degraded must be imported into the lysosome via specific pathways, and the hydrolases carrying out the task must also be sorted from other proteins and are translocated by means of transport vesicles. Prokaryotic cells, possessing neither membrane-bound compartments nor vesicular transport systems, have developed a different form of compartmentalization, namely self- or autocompartmentalization (65Lupas A Flanagan J.M Tamura T Baumeister W Self-compartmentalizing proteases.Trends Biochem. Sci. 1997; 22 (b): 399-404Abstract Full Text PDF PubMed Scopus (197) Google Scholar). This principle is seen at work in several unrelated proteases that have all converged toward a common architecture in which proteolytic subunits self-assemble to form barrel-shaped complexes. These enclose inner cavities, which are several nanometers in diameter and harbor the active sites. Access to these inner compartments is usually restricted to unfolded polypeptides, which can pass through the narrow pores or channels guarding the entrance. The target proteins thus require interaction with a machinery capable of binding and presenting them in an unfolded form to the proteolytic core complexes; these interactions may be of either a transient or a continuous nature. Since protein folding and unfolding are closely related mechanistically, it is assumed, but not proven, that this task is performed by ATPase complexes, which bear some resemblance to the chaperonins and have been referred to as “reverse chaperones” or “unfoldases” (61Lupas A Koster A.J Baumeister W Structural features of 26S and 20S proteasomes.Enz. Prot. 1993; 47: 252-273Crossref PubMed Scopus (0) Google Scholar). Since their action requires the hydrolysis of ATP, protein degradation becomes energy-dependent, although the hydrolysis of the polypeptide chain itself is an exergonic process. Self-compartmentalizing proteases are common in all three domains of life: archaea, bacteria, and eukarya. This bears testimony to an old evolutionary principle. In fact, contrary to organelles such as the lysosome, self-compartmentalizing molecular devices offer far greater flexibility: when equipped with the appropriate localization signals, they can be deployed to different cellular locations in the cytosol or in the nucleus, wherever their action is needed. The advances made in recent years in understanding the structure of the proteasome and its mechanism of action has helped to shape the concept of self-compartmentalization, and the proteasome became the paradigm of this form of regulation. The first description of a “cylinder-shaped” complex with proteasome-like features dates back to the late sixties. The plethora of names given to it subsequently is a reflection of the problems that were encountered over a period of two decades in trying to define its biochemical properties and cellular functions. Enzymological studies revealed an array of distinct proteolytic activities and led to a consensus name, “multicatalytic proteinase” (20Dahlmann B Kuehn L Ishiura S Tsukahara T Sugita H Tanaka K Rivett A.J Hough R.F Rechsteiner M Mykles D.L et al.The multicatalytic proteinase a high-Mr endopeptidase.Biochem. J. 1988; 255: 750-751PubMed Google Scholar). This name, however, was soon replaced by a new one, the proteasome (6Arrigo A.P Tanaka K Goldberg A.L Welch W.J Identity of the 19S “prosome” particle with the large multifunctional protease complex of mammalian cells (the proteasome).Nature. 1988; 331: 192-194Crossref PubMed Scopus (300) Google Scholar), emphasizing its character as a molecular machine (for a brief account of the early history of this field, see8Baumeister W Cejka Z Kania M Seemüller E The proteasome a macromolecular assembly designed to confine proteolysis to a nanocompartment.Biol. Chem. 1997; 378: 121-130PubMed Google Scholar). At about the same time, it was found that the occurrence of proteasomes was not restricted to eukaryotic cells. A compositionally simpler, but structurally strikingly similar proteolytic complex was found in the archaeon Thermoplasma acidophilum (21Dahlmann B Kopp F Kuehn L Niedel B Pfeifer G Hegerl R Baumeister W The multicatalytic proteinase (prosome) is ubiquitous from eukaryotes to archaebacteria.FEBS Lett. 1989; 251: 125-131Abstract Full Text PDF PubMed Scopus (247) Google Scholar), which later took a pivotal role in elucidating the structure and enzymatic mechanism of the proteasome. Meanwhile, proteasomes have been identified in several archaea (e.g., see66Maupin-Furlow J.A Ferry J.G A proteasome from the methanogenic archaeon Methanosarcina thermophila.J. Biol. Chem. 1995; 270: 28617-28622Crossref PubMed Scopus (62) Google Scholar), and the forthcoming sequence data of more genomes will reveal how common they are within this domain. The first evidence for the existence of proteasomes in bacteria was provided by a database search and sequence comparison (62Lupas A Zwickl P Baumeister W Proteasome sequences in eubacteria.Trends Biochem. Sci. 1994; 19: 533-534Abstract Full Text PDF PubMed Scopus (58) Google Scholar), which indicated that two types of proteasomes might exist in bacteria, one represented by the Escherichia coli hslV gene (16Chuang S.E Burland V Plunkett G Daniels D.L Blattner F.R Sequence analysis of 4 new heat-shock genes constituting the hslu and hslv operons in Escherichia coli.Gene. 1993; 134: 1-6Crossref PubMed Scopus (134) Google Scholar) and one by a gene (prcB) found in the Mycobacterium leprae genome. Subsequent biochemical and structural studies confirmed the existence of two types of proteasomes in bacteria: HslV and its homologs, although clearly related to (β-type) proteasomal subunits, form a simpler complex in which two six-membered rings form the proteolytic core and associate directly with an ATPase of the Clp family (ClpX/HslU) (9Bochtler M Ditzel L Groll M Huber R Crystal structure of heat shock locus V (HslV) from Escherichia coli.Proc. Natl. Acad. Sci. USA. 1997; 94: 6070-6074Crossref PubMed Scopus (162) Google Scholar, 79Rohrwild M Pfeifer G Santarius U Müller S.A Huang H.-C Engel A Baumeister W Goldberg A.L The ATP-dependent HslVU protease from Escherichia coli is a four-ring structure resembling the proteasome.Nature Struct. Biol. 1997; 4: 133-139Crossref PubMed Scopus (169) Google Scholar). The second type, represented by Mycobacterium and Rhodococcus, is possibly restricted in its occurrence to actinomycetales. These proteasomes form a complex indistinguishable in its general architecture from eukaryotic or archaeal 20S proteasomes (91Tamura T Nagy I Lupas A Lottspeich F Cejka Z Schoofs G Tanaka K Demot R Baumeister W The first characterization of a eubacterial proteasome the 20S complex of Rhodococcus.Curr. Biol. 1995; 5: 766-774Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar, 111Zühl F Tamura T Dolenc I Cejka Z Nagy I De Mot R Baumeister W Subunit topology of the Rhodococcus proteasome.FEBS Lett. 1997; 400 (a): 83-90Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). It is conceivable that the actinomycetales have acquired the proteasome genes by horizontal gene transfer after their separation from other Gram-positive bacteria, possibly from a eukaryotic organism, especially considering that many actinomycetales live in symbiotic association with eukaryotes or are pathogens (64Lupas A Zühl F Tamura T Wolf S Nagy I DeMot R Baumeister W Eubacterial proteasomes.Mol. Biol. Rep. 1997; 24 (a): 125-131Crossref PubMed Google Scholar). Under normal growth conditions, proteasomes or proteasome-related complexes appear not to be essential in eubacteria. M. smegmatis cells in which proteasome genes are deleted are viable and phenotypically indistinguishable from wild-type cells (53Knipfer N Shrader T.E Inactivation of the 20S proteasome in Mycobacterium smegmatis.Mol. Microbiol. 1997; 25: 375-383Crossref PubMed Scopus (76) Google Scholar). This is different from the situation in yeast, where the disruption of 13 out of the 14 proteasome genes is lethal (e.g., see 47Hilt W Wolf D.H Proteasomes of the yeast S. cerevisiaegenes, structure and functions.Mol. Biol. Rep. 1995; 21: 3-10Crossref PubMed Scopus (58) Google Scholar), but is consistent with the observation that proteasome-related genes were not found in some recently sequenced eubacterial genomes (e.g., Mycoplasma genitalium). Archaeal proteasomes are built of 14 copies each of two different but related subunits, α and β, whereas eukaryotic proteasomes contain two copies each of 14 different subunits, which, based on their sequence similarity, can be divided into an α-type and a β-type group. The subunits are arranged into four seven-membered rings, with the α-type subunits forming the two outer rings, and the β-type subunits the two inner rings. Collectively, they form a barrel-shaped complex, 15 nm in length and 11 nm in diameter (Figure 1a), which encloses three internal cavities, approximately 5 nm in diameter bounded by four narrow constrictions. The central cavity is formed by the two adjacent β rings, while the two outer cavities (the “antechambers”) are formed jointly by one α and one β ring. As anticipated from their sequence similarity, the noncatalytic α- and the catalytic β-type subunits have the same fold (87Seemüller E Lupas A Stock D Löwe J Huber R Baumeister W Proteasome from Thermoplasma acidophiluma threonine protease.Science. 1995; 268: 579-582Crossref PubMed Scopus (567) Google Scholar, 43Groll M Ditzel L Löwe J Stock D Bochtler M Bartunik H.D Huber R Structure of 20S proteasome from yeast at 2.4 Å resolution.Nature. 1997; 386: 463-471Crossref PubMed Scopus (1826) Google Scholar): a four-layer α and β structure with a central five-stranded β sandwich flanked on either side by α helices (Figure 1a). Helices 1 and 2 mediate the interaction of the α- and β rings (β-trans-α) by intercalating in a wedge-like fashion. Helices 3 and 4, which are located on the opposite side, provide the dominant contacts between the two β rings (β-trans-β). While this general architecture is the same in the Thermoplasma and in the yeast proteasome, there is a large number of additional specific α-cis, β-cis, β-trans-α, and β-trans-β contacts in the yeast proteasome as detailed in Groll et al., 1997. Together with the propeptides, these contacts seem to ensure that the assembly proceeds in an orderly fashion, that is, that each of the 14 different subunits takes its correct place (see below). The main difference between α- and β-type subunits is due to a highly conserved N-terminal extension of the α-type subunits, part of which (residues 20–30) forms an α helix (HO) across the top of the central β sandwich (see Figure 1a). The function of the N-terminal extension is not clear, but its location at the top of the α rings close to the entrance to the antechambers indicates that it may be important for the translocation of substrate or for interactions between the proteasome and its regulatory complexes. Instead of this N-terminal extension, β-type subunits have prosequences of varying lengths, which are removed during proteasome assembly, thus rendering the cleft between the central β sandwich freely accessible from the central cavity. Although the proteasome fold was initially believed unique, it has subsequently been shown to be prototypical of a new family of proteins referred to as the Ntn (N-terminal nucleophile) hydrolases (11Brannigan J.A Dodson G Duggleby H.J Moody P.C.E Smith J.L Tomchick D.R Murzin A.G A protein catalytic framework with an N-terminal nucleophile is capable of self-activation.Nature. 1995; 378: 416-419Crossref PubMed Scopus (513) Google Scholar). A common feature of the Ntn-hydrolases is a “single residue” catalytic center, which is freed by the autocatalytic removal of the prosequence. The identification of the N-terminal threonine of the β subunit of the Thermoplasma proteasome as both the catalytic nucleophile and the primary proton acceptor came as a surprise (87Seemüller E Lupas A Stock D Löwe J Huber R Baumeister W Proteasome from Thermoplasma acidophiluma threonine protease.Science. 1995; 268: 579-582Crossref PubMed Scopus (567) Google Scholar, 87Seemüller E Lupas A Stock D Löwe J Huber R Baumeister W Proteasome from Thermoplasma acidophiluma threonine protease.Science. 1995; 268: 579-582Crossref PubMed Scopus (567) Google Scholar), since, until then, the proteasome was widely assumed to be an unusual type of serine protease. Beside the N-terminal threonine, β subunits require several other residues (Glu-17, Lys-33, Asp-166) for activity, although their exact roles remain to be clarified. Lys-33 and Glu-17 form a salt bridge across the bottom of the active site and may participate in the delocalization of the threonine side-chain proton by forming a charge relay system. Further evidence supporting the role of the N-terminal threonine came from work with the antibiotic lactacystin, or more accurately, its active form clasto-lactacystin β-lactone (26Dick L.R Cruikshank A.A Grenier L Melandri F.D Nunes S.L Stein R.L Mechanistic studies on the inactivation of the proteasome by lactacystin.J. Biol. Chem. 1996; 271 (a): 7273-7276Crossref PubMed Scopus (347) Google Scholar), which covalently reacts with the Thr-1 of a specific subset of β-type subunits of mammalian proteasomes (34Fenteany G Standaert R.F Lane W.S Choi S Corey E.J Schreiber S.L Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin.Science. 1995; 268: 726-731Crossref PubMed Scopus (1460) Google Scholar). The lactacystin experiments as well as recent mutational studies with yeast and mammalian β-type subunits (15Chen P Hochstrasser M Autocatalytic subunit processing couples active site formation in the 20S proteasome to completion of assembly.Cell. 1996; 86: 961-972Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar, 84Schmidtke G Kraft R Kostka S Henklein P Frömmel C Löwe J Huber R Kloetzel P.M Schmidt M Analysis of mammalian 20S proteasome biogenesis the maturation of β-subunits is an ordered two-step mechanism involving autocatalysis.EMBO J. 1996; 15: 6887-6898Crossref PubMed Google Scholar, 5Arendt C.S Hochstrasser M Identification of the yeast 20S proteasome catalytic centers and subunit interactions required for active-site formation.Proc. Natl. Acad. Sci. USA. 1997; 94: 7156-7161Crossref PubMed Scopus (227) Google Scholar) confirmed a prediction made on the basis of sequence comparisons that the proteolytic mechanism is the same in eukaryotic and in Thermoplasma proteasomes (87Seemüller E Lupas A Stock D Löwe J Huber R Baumeister W Proteasome from Thermoplasma acidophiluma threonine protease.Science. 1995; 268: 579-582Crossref PubMed Scopus (567) Google Scholar). From the conservation pattern of the active site residues, it was further deduced that, of the seven β-type subunits in an individual eukaryotic proteasome, only three are proteolytically active (see Figure 2a). Since each of them is present in two copies, the number of active sites in the central cavity is 6, instead of 14 as in the Thermoplasma proteasome. The reasons for this reduction in the number of active sites are unclear, and also, the function of the “inactive” β-type subunits awaits further clarification. Mutagenesis and chemical modification (e.g., see46Heinemeyer W Gruhler A Mohrle V Mahe Y Wolf D.H PRE2, highly homologous to the human major histocompatibility complex-linked RING10 gene, codes for a yeast proteasome subunit necessary for chymotryptic activity and degradation of ubiquitinated proteins.J. Biol. Chem. 1993; 268: 5115-5120Abstract Full Text PDF PubMed Google Scholar, 32Enenkel C Lehmann H Kipper J Guckel R Hilt W Wolf D.H PRE3, highly homologous to the human major histocompatibility complex-linked LMP2 (RING12) gene, codes for a yeast proteasome subunit necessary for the peptidylglutamyl-peptide hydrolyzing activity.FEBS Lett. 1994; 341: 193-196Abstract Full Text PDF PubMed Scopus (69) Google Scholar, 5Arendt C.S Hochstrasser M Identification of the yeast 20S proteasome catalytic centers and subunit interactions required for active-site formation.Proc. Natl. Acad. Sci. USA. 1997; 94: 7156-7161Crossref PubMed Scopus (227) Google Scholar) have shown that each of the three major activities of eukaryotic proteasomes (chymotrypsin-like activity, trypsin-like activity, and peptidylglutamyl peptide hydrolyzing activity), as defined by the degradation of short fluorgenic peptides, can be abolished by modifying either an active or an inactive subunit. It is not clear whether special pairs of active and inactive subunits exist, which interact allosterically, or whether mutations of inactive subunits simply tend to cause structural perturbations with a high likelihood of affecting the neighboring active subunits (see Figure 2b). Another feature apparently distinguishing the yeast proteasome and the Thermoplasma proteasome structure relates to the openings that give access to the inner cavities. The crystal structure of the Thermoplasma proteasome revealed the existence of a channel located along the 7-fold axis (Figure 1b). This channel is defined by a turn-forming segment with Tyr-126 at a strategic position; collectively, the seven turns form a hydrophobic annulus well suited for the translocation of an unfolded polypeptide. Direct evidence that this channel is the port of entry was obtained by electron microscopic visualization of a Nanogold-labeled insulin β chain caught in transit; the relatively bulky (approximately 2 nm) gold label prevents it from slipping across the channel into the antechamber (103Wenzel T Baumeister W Conformational constraints in protein degradation by the 20S proteasome.Nat. Struct. Biol. 1995; 2: 199-204Crossref PubMed Scopus (183) Google Scholar). In the yeast proteasome, this channel is occluded by the N-terminal residues of the α subunits, which are disordered in the Thermoplasma proteasome. On the other hand, the yeast proteasome has small openings situated at the interface between α and β rings; this led to speculations that the side windows may be used to take up substrate. However, it is not very likely that such highly conserved structures use radically different routes for translocation. Moreover, the side windows would be rather ill-positioned for the uptake of polypeptides when the 20S proteasome associates with its regulatory complexes. It is more likely, therefore, that eukaryotic proteasomes use the central channel, which then must undergo a conformational change. It is noteworthy in this context that eukaryotic but not Thermoplasma proteasomes are purified in a latent state and need to be activated by chaotropic agents or heat. These treatments may selectively unfold the N-terminal sequence, resulting in an opening of the channel. Under physiological conditions, a gating of the channel could be controlled by regulatory complexes that dock to the two termini of the 20S complex. While the side windows are unlikely to be used for the entry of substrate, it is possible that they have a role in discharging degradation products. Polypeptides to be degraded must wind their way through a system of internal cavities and constrictions until they reach the active sites in the central cavity, at least 8–10 nm away from the orifice at the center of the α ring (see Figure 3). The underlying mechanism of translocation is unknown, as is the precise role of the two antechambers. One could envisage that when the 20S proteasome is associated with regulatory complexes which unfold substrate proteins in an ATP-dependent manner, unfolding and translocation of the polypeptide are coupled, and thus, that the unfolded chain is “pushed” into the 20S core. However, when the unfolded polypeptide alone is offered to the 20S proteasome in vitro, it is capable of degrading it; thus, the translocation is not strictly energy-dependent. The structural properties of the interior of the proteasome should bias the random walk of the polypeptide chain toward the active side clefts; the antechambers, which have a volume of ∼59 nm3, must be able to maintain the polypeptide in an unfolded form as it passes through them. It is possible that the existence of constrictions segregating the front end from the rear end of a translocating polypeptide chain serves as a means to prevent refolding. The crystal structure of the chaperonin GroEL in complex with its co-chaperonin GroES (107Xu Z Horwich A.L Sigler P.B The crystal structure of the asymmetric GroEL-ES-(ADP)7 chaperonin complex.Nature. 1997; 388: 741-750Crossref PubMed Scopus (980) Google Scholar; for review, see 12Bukau B Horwich A.L The Hsp70 and Hsp60 chaperone machines.Cell. 1998; 92 (this issue): 351-366Abstract Full Text Full Text PDF PubMed Scopus (2299) Google Scholar, this issue of Cell) illustrates how properties of cavities may determine interactions with nonnative polypeptides. Upon binding of GroES, one of the two heptameric GroEL rings (the cis ring) undergoes a major structural rearrangement and, concomitantly, the properties of the cis cavity change: while the trans cavity is lined with hydrophobic residues, favoring the interaction with nonnative polypeptides, the cis cavity exposes mostly polar residues and thus repels nonnative polypeptides. In terms of overall hydrophobicity, the antechambers of the proteasome assume an intermediate position. Upon careful inspection, one may discern an array of paths where hydrophobic residues are clustered (Figure 3); in spite of their meandering appearance, these paths seem to connect the α-ring channel with the inner constriction and thus may give direction to a polypeptide chain on its way into the central cavity. The central cavity, which is less hydrophobic than the antechambers, has a volume of ∼84 nm3, allowing it, in principle, to accommodate a single folded protein of ∼70 kDa; a loosely packed unfolded polypeptide requires much more space. Since polypeptides can only enter the cavity one after the other, the central cavity will not usually accommodate more than one polypeptide at a time. The confinement of the substrate to this cavity with its 6–14 active sites provides the structural basis for the processive mode of action of the proteasome; it completes the degradation of one polypeptide before attacking the next (2Akopian T.N Kisselev A.F Goldberg A.L Processive degradation of proteins and other catalytic properties of the proteasome from Thermoplasma acidophilum.J. Biol. Chem. 1997; 272: 1791-1798Crossref PubMed Scopus (171) Google Scholar). Eukaryotic proteasomes have three major peptidase activities that have been defined using short fluorogenic peptide substrates: a chymotrypsin-like activity, which cleaves after hydrophobic residues, a trypsin-like activity, which cleaves after basic residues, and a peptidylglutamyl peptide-hydrolyzing activity, which cleaves after acidic residues. Two additional specificities have been identified in mammalian proteasomes, cleaving after branched chain residues and between small neutral amino acids (for review, see13Cardozo C Catalytic components of the bovine pituitary multicatalytic proteinase complex (proteasome).Enz. Prot. 1993; 47: 296-305PubMed Google Scholar). The proteasomes of Thermoplasma and of the bacterium Rhodococcus have only chymotrypsin-like activity, consistent with the fact that they have only one type of active site (22Dahlmann B Kuehn L Grziwa A Zwickl P Baumeister W Biochemical properties of the proteasome from Thermoplasma acidophilum.Eur. J. Biochem. 1992; 208: 789-797Crossref PubMed Scopus (62) Google Scholar, 91Tamura T Nagy I Lupas A Lottspeich F Cejka Z Schoofs G Tanaka K Demot R Baumeister W The first characterization of a eubacterial proteasome the 20S complex of Rhodococcus.Curr. Biol. 1995; 5: 766-774Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar). Mutational studies and the crystal structure of the yeast proteasome can be used to assign these activities to distinct subunits (see Figure 2), but they have little (if any) relevance to the cleavage specificity of protein substrates. Degradation studies performed with Thermoplasma proteasomes (104Wenzel T Eckerskorn C Lottspeich F Baumeister W Existence of a molecular ruler in proteasomes suggested by analysis of degradation products.FEBS Lett. 1994; 349: 205-209Abstract Full Text PDF PubMed Scopus (145) Google Scholar) and eukaryotic proteasomes (e.g., see25Dick L.R Aldrich C Jameson S.C Moomaw C.R Pramanik B.C Doyle C.K DeMartino G.N Bevan M.J Forman J.M Slaughter C.A Proteolytic processing of ovalbumin and β-galactosidase by the proteasome to yield antigenic peptides.J. Immunol. 1994; 152: 3884-3894PubMed Google Scholar, 31Ehring B Meyer T.H Eckerskorn C Lottspeich F Tampé R Effects of major-histocompatibility-complex-encoded subunits on the peptidase and proteolytic activities of human 20S proteasomes.Eur. J. Biochem. 1996; 235: 404-415Crossref PubMed Scopus (73) Google Scholar) have yielded cleavage patterns that do not correlate with the aforementioned specificities. Obviously, a classification of cleavage specificities using the residue directly adjacent to the cleavage site (the P1 position) falls short of reality. It was intriguing to observe that, in spite of cleaving protein substrates in a rather nonspecific manner, the generated products fell into a relatively narrow size range, averaging around 7–9 residues. This property, which is common to prokaryotic and eukaryotic proteasomes, led to the proposal that an intrinsic “molecular ruler” determines product length (103Wenzel T Baumeister W Conformational constraints in protein degradation by the 20S proteasome.Nat. Struct. Biol. 1995; 2: 199-204Crossref PubMed Scopus (183) Google Scholar). It was envisaged that the distance between active sites, acting in concert, could provide the physical basis of such a ruler. The crystal structure of the Thermoplasma proteasome revealed a distance of 2.8 nm between neighboring active sites corresponding to a hepta- or octa-peptide in an extended conformation; thus, it seemed to provide strong evidence in support of the molecular ruler hypothesis. On the other hand, recent more quantitative analyses of product lengths (52Kisselev A.F Akopian T.N Goldberg A.L Protein degradation by the 20S proteasome generates a spectrum of peptides ranging from 3 to 30 residues in length.J. Biol. Chem. 1998; in pressGoogle Scholar), while in agreement with the average length, showed larger size variations, which may be difficult to reconcile with a purely geometry-based ruler. It is now well established that the proteasome has an important role in generating immunocompetent peptides to be displayed by the MHC class I complex. Obviously, the evolution of the proteasome predates the evolution of the immune system, and the availability of peptides between 7 and 9 residues long must have had a profound influence on the evolution of the MHC class I system (70Niedermann G Grimm R Geier E Maurer M Realini C Gartmann C Soll J Omura S Rechsteiner M.C Baumeister W Eichmann K Potential immunocompetence of proteolytic fragments produced by proteasomes before evolution of the vertebrate immune system.J. Exp. Med. 1997; 186: 209-220Crossref PubMed Scopus (79) Google Scholar). In turn, the proteasome seems to have responded to the need of the immune system for specific peptides by developing variants of some of its β-type subunits, which upon induction by γ-interferon can replace their constitutive counterparts in the 20S complex, thus allowing further modulation of specificity (for reviews, see38Goldberg A.L Gaczynska M Grant E Michalek M Rock K.L Functions of the proteasome in antigen presentation.Cold Spring Harb. Symp. Quant. Biol. 1995; 60: 479-490Crossref PubMed Scopus (45" @default.
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• W1991930087 title "The Proteasome: Paradigm of a Self-Compartmentalizing Protease" @default.
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