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• W2003849992 abstract "Most short-lived proteins in eukaryotes are degraded through the same mechanism: an initial tagging step in which the substrate is multiubiquitinated, followed by degradation via the proteasome (16Rubin D.M Finley D Curr. Biol. 1995; 5: 854-858Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 4Coux O Tanaka K Goldberg A Annu. Rev. Biochem. 1996; 65: 801-847Crossref PubMed Scopus (2178) Google Scholar, 8Hochstrasser M Annu. Rev. Genet. 1996; 30: 405-439Crossref PubMed Scopus (1420) Google Scholar, 1Baumeister W Lupas A Curr. Opin. Struct. Biol. 1997; 7: 273-278Crossref PubMed Scopus (64) Google Scholar). It has recently become clear that many key regulatory factors such as cyclins, cyclin-dependent kinase inhibitors, p53, and NF-κB, are controlled through this pathway in a signal-dependent or cell cycle–dependent fashion. Ubiquitination has also been implicated in the regulation of DNA repair, transcriptional silencing, neuronal pathfinding, terminal differentiation, and long-term facilitation of withdrawal reflexes in Aplysia. As expected for a system that participates in so many processes, the ubiquitin-proteasome pathway is complex, involving so far about 100 known components. The most intricate component of the pathway, with over 30 distinct subunits, is the proteasome. Its ubiquitin dependence, ATP dependence, and complex structure (Figure 1A; 13Peters J.-M Cejka Z Harris R Kleinschmidt J.A Baumeister W J. Mol. Biol. 1993; 234: 932-937Crossref PubMed Scopus (209) Google Scholar) all set it apart from simple and well-understood extracellular proteases such as trypsin.Figure 2HslVU and ClpAP ProteasesShow full captionColor scheme as in Figure 1. Compiled with assistance from L. Ditzel, R. Huber, H. Kwon, and T. Ellenberger.(A) Electron micrograph of HslVU. The identity of the uppermost, asymmetrically distributed mass is unknown.(B) Cut-away view of HslV.(C) Ribbon diagram of two HslV subunits. Note proximity of the active-site Thr-1 to the pore. The C terminus has been truncated to reduce the image size.(D) Electron micrograph of ClpAP (Kessel et al. 1995). Each cap particle has a distal and proximal ring of mass density. These may correspond to the two ATPase domains of ClpA.(E) Cut-away view of ClpP.(F) Ribbon diagram of two ClpP subunits.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Color scheme as in Figure 1. Compiled with assistance from L. Ditzel, R. Huber, H. Kwon, and T. Ellenberger. (A) Electron micrograph of HslVU. The identity of the uppermost, asymmetrically distributed mass is unknown. (B) Cut-away view of HslV. (C) Ribbon diagram of two HslV subunits. Note proximity of the active-site Thr-1 to the pore. The C terminus has been truncated to reduce the image size. (D) Electron micrograph of ClpAP (Kessel et al. 1995). Each cap particle has a distal and proximal ring of mass density. These may correspond to the two ATPase domains of ClpA. (E) Cut-away view of ClpP. (F) Ribbon diagram of two ClpP subunits. Proteasomes actually employ a remarkably novel mechanism, the general nature of which became apparent from the crystal structure of the proteasomal core particle from the archaeon T. acidophilum (12Löwe J Stock D Jap B Zwickl P Baumeister W Huber R Science. 1995; 268: 533-539Crossref PubMed Scopus (1335) Google Scholar). The telling aspect of the T. acidophilum core particle was the positioning of the proteolytic active sites within the hollow interior of the cylinder (Figure 1B). The side walls of the core complex function as a topological barrier, forming a lumenal space from which cytoplasmic proteins are excluded, a type of function usually performed by lipid membranes. The T. acidophilum core particle contains two classes of subunits, α and β, located in the outer and inner rings, respectively (Figure 1A). The β subunits contain the proteolytic active sites (Figure 1B). The only channels opening into the lumen, and presumably the sites of substrate entry, are at the opposite ends of the cylinder (Figure 1B). In the holoenzyme form of ATP-dependent proteases, such channels do not open out onto the cytoplasm, but rather into a second particle, the regulatory complex (Figure 1AFigure 2A, and Figure 2D). In prokaryotes, regulatory complexes are composed of homomeric assemblies of ATPases, whereas in the eukaryotic proteasome they are more complex, containing approximately 20 distinct subunits, six of them ATPases. The regulatory complexes, and the ATPases in particular, seem positioned to control the entry of substrates into the lumen of the core particle. Presumably each regulatory complex has its own channel, which should be continuous with that of its associated core particle. The complexity of eukaryotic proteasome-regulatory complexes partly reflects their capacity both to bind multiubiquitin chains and to disassemble them into ubiquitin monomers (18van Nocker S Sadis S Rubin D.M Glickman M Fu H Coux O Wefes I Finley D Vierstra R.D Mol. Cell. Biol. 1996; 16: 6020-6028Crossref PubMed Scopus (347) Google Scholar, 10Lam Y.A Xu W DeMartino G.N Cohen R.E Nature. 1997; 385: 737-740Crossref PubMed Scopus (357) Google Scholar, 14Piotrowski J Beal R Hoffman L Wilkinson K.D Cohne R.E Pickart C.M J. Biol. Chem. 1997; 272: 23712-23721Crossref PubMed Scopus (181) Google Scholar). In E. coli, there is no ubiquitin-tagging mechanism and the regulatory complexes contain only ATPase subunits. There are at least five ATP-dependent proteases in E. coli, in contrast to the eukaryotic cytoplasm, where the proteasome is the only known ATP-dependent protease. For the bacterial proteases, the selectivity of a given complex is determined not by the core particle but by the ATPase subunit (or domain) and its direct interaction with substrates (see5Gottesman S Maurizi M.R Wickner S Cell, this issue. 1997; Google Scholar [this issue of Cell). Thus, in bacteria, sequence motifs that signal degradation of a protein may typically correspond to binding sites for the ATPases, whereas in eukaryotes, degradation signals are characteristically targets of the ubiquitination machinery and do not seem to be recognized by the proteasome itself. However, we expect that in the eukaryotic proteasome, the ATPases also interact with substrate but play a less critical role in substrate selection. Given that substrates bind initially to the regulatory complex and are subsequently cleaved within the lumen of the core particle, there must be an intermediate step in which the substrate travels from one subcompartment of the protease to the other—a distance of more than 60 Å. This process may largely account for the strict ATP dependence exhibited by this class of proteases. Although ATP hydrolysis could in principle directly provide the energy for translocation, the net forward progress of translocation might result more simply from hydrolysis of the substrate at the distal end of the channel. Another possible role for ATP is suggested by the dimensions of the channel—13 Å in the case of T. acidophilum. Folded proteins are far too large to pass through such a channel (Wentzel et al., 1995; 5Gottesman S Maurizi M.R Wickner S Cell, this issue. 1997; Google Scholar), even allowing for uncertainty as to its exact dimensions. This leads to the prediction of a fourth step in the process, an unfolding event that must be executed prior to substrate translocation. Thus, one role for ATP hydrolysis may be to assist in substrate unfolding. ATP hydrolysis and an unfolded state of the translocation substrate are well-established requirements for protein translocation into the ER and the mitochondrion. In contrast to these multicomponent systems, ATP-dependent proteases appear to function as self-contained protein translocation devices. Translocation probably commits the protein to degradation, since the proteolytic active sites of the ATP-dependent proteases are relatively nonspecific and are present at concentrations of >100 mM within the lumen. An early indication that the interaction between regulatory particles and core particles is more complex than described above was the finding that the activity of core particles in hydrolyzing small peptide substrates was activated in the presence of regulatory particles. Long taken as an indication of an allosteric effect of the regulatory complex on the proteolytic active sites of the core particle, this effect now seems more likely to reflect gating of the channel, at least in the case of the proteasome. Evidence for a closed state of the channel was provided by the structure of the yeast core particle. Remarkably, it shows no evidence for any opening into the lumen (Figure 1D). The presumed entry site of the channel is occupied by the N termini of five α subunits, which converge in an irregular pattern near the center of the cylinder's face (Figure 1E). The channel could potentially be opened by an outward migration of the N termini. The simplest mechanism for gating of the yeast channel is one in which it is directed by assembly of the core particle and the regulatory complex to form the 26S proteasome. This type of gating would be analogous to assembly-dependent formation of the Sec61 protein translocation channel of the ER (7Hanein D Matlack K.E Jungnickel B Plath K Kalies K.-U Miller K.R Rapoport T Akey C.W Cell. 1996; 87: 721-732Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar). A more interesting possibility is that the channel can assume open and closed states within the holoenzyme as well. In the case of Sec61, the assembled complex is subject to gating, which is controlled by the presence of nascent polypeptide. Proteolytic substrates might similarly regulate gating of the proteasome holoenzyme. Other ligands of the regulatory complex, such as ATP and multiubiquitin chains, could also potentially influence the state of the channel. The N termini of the α subunits are disordered and not visualized in the T. acidophilum proteasome crystal. Because these segments must be present near or within the channel (Figure 1C), the channel may not be as open as it appears. A well-defined channel has been found in HslV, the core component of the HslVU protease of E. coli (Figure 2A; 15Rohrwild M Pfeifer G Santarius U Müller S.A Huang H.-C Engel A Baumeister W Goldberg A.L Nat. Struct. Biol. 1997; 4: 133-139Crossref PubMed Scopus (172) Google Scholar). A single gene product, arranged into two six-membered rings, forms the core complex (Figure 2B). The bulk of its structure can be neatly superimposed on those of the proteolytically active β subunits of yeast and T. acidophilum proteasomes (Figure 2B; 2Bochtler M Ditzel L Groll M Huber R Proc. Natl. Acad. Sci. USA. 1997; 94: 6070-6074Crossref PubMed Scopus (164) Google Scholar). At the cylinder face, however, its structure mimics that of the α rather than β subunits insofar as the HslV subunits converge to form a channel whose diameter exceeds that of the T. acidophilum channel by only 2 Å (Figure 2C). HslV and the proteolytically active subunits of T. acidophilum and S. cerevisiae are founding members of a novel protease family, the threonine proteases. Another novel feature of these subunits is the placement of the active site threonine directly at the N terminus of the protein. Do evolutionarily unrelated ATP-dependent proteases also have protein translocation channels? There are dramatic structural differences between HslV and the ClpP protease of E. coli (Figure 2C and Figure 2F), and the active-site nucleophile in ClpP is Ser-97 rather than Thr-1 (Table 1). Yet ClpP conforms to the pattern in forming a cylindrical structure with narrow, 10-Å channels at the faces (Figure 2E; 19Wang J Hartling J.A Flanagan J.M Cell, this issue. 1997; Google Scholar). With a disordered N-terminal domain in the region of the channel (Figure 2F), it calls to mind the T. acidophilum structure particularly.Table 1Structural Features of Compartmentalized Proteolytic Core ParticlesProteaseOrganismNumber of RingsSubunits per RingDistinct SubunitsChannel Width (Å)aChannel diameters in the isolated core particles may differ for those of the holoenzymes, which are thus far unknown.Mol Weight (kDa)Active Site NucleophileProteasomeS. cerevisiae4714closed750Thr-1ProteasomeT. acidophilum47213–17670Thr-1HslVE. coli26119225Thr-1ClpPE. coli27110305Ser-97Gal6S. cerevisiae23122300Cys-73TricornT. acidophilum23125–30720Ser-965?LAPB. taurus2317–10325Zn-coördinated OH−a Channel diameters in the isolated core particles may differ for those of the holoenzymes, which are thus far unknown. Open table in a new tab The example of ClpP illustrates that, while ATP-dependent proteases may have distinct catalytic mechanisms for peptide bond cleavage, and unrelated core components, they share one basic feature: a barrel-like structure with closely packed side walls and an axial channel that is narrow enough to exclude folded proteins from the lumenal domain. In all cases, ATPase-containing regulatory complexes (5Gottesman S Maurizi M.R Wickner S Cell, this issue. 1997; Google Scholar) cover the outer port of the channel and presumably regulate the entry of substrates into the lumen. Although axial channels may be a general feature of ATP-dependent proteases, the structural features of the channels vary. An internal loop forms the channel in HslV, whereas the other channels are formed by N-terminal segments. Only in the case of yeast is the channel fully occluded in the crystal structure in a manner that suggests a gating mechanism (6Groll M Ditzel L Löwe J Stock D Bochtler M Bartunik H.D Huber R Nature. 1997; 386: 463-471Crossref PubMed Scopus (1873) Google Scholar). Recently, two other intracellular proteases, the Gal6 protease of S. cerevisiae and the tricorn protease of T. acidophilum, have been likened to the proteasome in their structural organization (Figure 3A and Figure 3B). In the case of the hexameric protease Gal6, the crystal structure clearly shows a narrow (22 Å) axial channel leading to a cavity containing the active sites (9Joshua-Tor L Xu H.E Johnston S.A Rees D.C Science. 1995; 269: 945-950Crossref PubMed Scopus (117) Google Scholar). Tricorn similarly exists as a hexamer but is also capable of further assembly into a remarkable capsid-like structure of approximately 50 nm in diameter (17Tamura T Tamura N Cejka Z Hegerl R.H Lottspeich F Baumeister W Science. 1996; 274: 1385-1389Crossref PubMed Scopus (97) Google Scholar). Tricorn can also assemble with additional activating factors that themselves have peptidase activity (17Tamura T Tamura N Cejka Z Hegerl R.H Lottspeich F Baumeister W Science. 1996; 274: 1385-1389Crossref PubMed Scopus (97) Google Scholar). However, these factors do not have ATPase activity and have not been shown to cap the tricorn channel. Thus, the similarity of tricorn (and Gal6) to the proteasome may not extend to the regulatory complex. If ATP-dependent protein unfolding is a prerequisite for translocating protein substrates into the lumen, how could these proteases function? We suggest that there are two distinct classes of compartmentalized cytoplasmic proteases, ATP-dependent and ATP-independent. The latter class may be specialized in the hydrolysis of small molecules that can freely permeate the channel. For these enzymes, active site sequestration may enhance specificity by ensuring that they act on peptides rather than proteins. Is active site compartmentalization a feature of still other cytoplasmic peptidases? What may have been the first compartmentalized protease to be described is actually an exopeptidase (3Burley S.K David P.R Taylor A Lipscomb W.N Proc. Natl. Acad. Sci. USA. 1990; 87: 6878-6882Crossref PubMed Scopus (209) Google Scholar). This passed largely unnoticed because it was reported before the proteasome structure had highlighted the significance of compartmentalization. Leucine aminopeptidase (LAP) is a hexameric enzyme with a three-membered ring structure, like Gal6 and tricorn (Table 1). LAP has six twisted channels that branch off from the equatorial plane (Figure 3C). Because it is induced by γ-interferon, like certain proteasome subunits, LAP may play a role in antigen presentation, perhaps acting to trim peptides released from the proteasome itself. In summary, active sites have been sequestered in a large and otherwise unrelated set of cytoplasmic proteases, a shared feature that apparently arose through convergent evolution. However, the existence of ATP-independent peptidases with compartmentalized structures suggests that such enzymes may have supplied evolutionary precursors for the multicomponent ATP-dependent proteases that now mediate most selective degradation of protein substrates. The channels may have served originally as protein-excluding molecular sieves but became sites for highly selective protein translocation when coupled to ATP-hydrolyzing regulatory complexes. With the development of such regulatory complexes, substrate recognition was displaced from the proteolytically active subunits to the ATPases. In eukaryotes, the major specificity factors for degradation are displaced still further with the development of the ubiquitin-conjugation machinery, which can function independently of the proteasome. Through such steps, simple proteases have been replaced by elaborately regulated proteolytic pathways." @default.
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• W2003849992 title "Protein Translocation Channels in the Proteasome and Other Proteases" @default.
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