Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteolytic cleavage of a limited number of cellular proteins is a central biochemical feature of apoptosis. Aspartate-specific cysteine proteases, the so-called 'caspases', are the main enzymes involved in this process. At least ten homologues of interleukin-1 beta converting enzyme (ICE), the first described human caspase, have been identified so far. The purified active proteins are heterodimers with a long and a short subunit derived from a common inactive precursor. Crystallized ICE has an original tetrameric structure. The various caspases tend to show high degrees of homology around the active site Cys. Proteolysis by caspases minimally requires a tetrapeptide substrate in which Asp is an absolute requirement in P1 position, the P4 substrate residue is unique to each homologue, and much more widespread amino acid substitution is observed in P2 and P3. Caspase activation might involve a proteolytic cascade similar to that of the coagulation cascade but the molecular ordering of these proteases in vivo remains to be established clearly. Calpains, serine proteases, granzymes and the proteasome-ubiquitin pathway of protein degradation are other proteolytic pathways that have been suggested to play a role in apoptosis. Substrate proteins can be either activated or degraded during cell death and the consequences of their cleavage remains mostly ill-understood. Nevertheless, the recent demonstration that protease inhibitors can rescue mice undergoing acute liver destruction indicates the accuracy of therapeutic strategies aiming to inhibit cell death-associated proteolysis.
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PMID:Proteases, proteolysis, and apoptosis. 955 23

Improperly processed secretory proteins are degraded by a hydrolytic system that is associated with the endoplasmic reticulum (ER) and appears to involve re-export of lumenal proteins into the cytoplasm for ultimate degradation by the proteasome. The chimaeric protein hGHDAF28, which contains a crippled glycosylphosphatidylinositol (GPI) C-terminal signal peptide, is degraded by a pathway highly similar to that for other ER-retained proteins and is characterized by formation of disulphide-linked aggregates, failure to reach the Golgi complex and intracellular degradation with a half life of approximately 2 h. Here we show that N-acetyl-leucinal-leucinal-norleucinal, MG-132 and lactacystin, all inhibitors of the proteasome, protect hGHDAF28; hGHDAF28 is still proteolytically cleaved in the presence of lactacystin or MG-132, by the removal of approximately 2 kDa, but the truncated fragment is not processed further. We demonstrate that the ubiquitination system accelerates ER-degradation of hGHDAF28, but is not essential to the process. Overall, these findings indicate that GPI quality control is mediated by the cytoplasmic proteasome. We also show that the presence of a cysteine residue in the GPI signal of hGHDAF28 is required for retention and degradation, as mutation of this residue to serine results in secretion of the fusion protein, implicating thiol-mediated retention as a mechanism for quality control of some GPI signals. Removal of the cysteine also prevents inclusion of hGHDAF28 in disulphide-linked aggregates, indicating that aggregate formation is an additional retention mechanism for this class of protein. Therefore our data suggest that an unpaired terminal cysteine is the retention motif of the hGHDAF28 GPI-processing signal and that additional information may be required for efficient engagement of ER quality control systems by the majority of GPI signals which lack cysteine residues.
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PMID:Proteasome and thiol involvement in quality control of glycosylphosphatidylinositol anchor addition. 957 58

Myeloperoxidase (MPO) deficiency is a common inherited disorder linked to increased susceptibility to infection and malignancy. We identified a novel missense mutation in the MPO gene at codon 173 whereby tyrosine is replaced with cysteine (Y173C) that is associated with MPO deficiency and assessed its impact on MPO processing and targeting in transfectants expressing normal or mutant proteins. Although the precursor synthesized by cells expressing the Y173C mutation (MPOY173C) was glycosylated, associated with the molecular chaperones calreticulin and calnexin, and acquired heme, it was neither proteolytically processed to mature MPO subunits nor secreted. After prolonged association with calreticulin and calnexin in the endoplasmic reticulum, MPOY173C was degraded. Furthermore, the 20S proteasome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinyl inhibited its degradation, suggesting that the proteasome mediates proteolysis of MPOY173C and, thus, participates in quality control in this novel form of hereditary MPO deficiency.
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PMID:A novel form of hereditary myeloperoxidase deficiency linked to endoplasmic reticulum/proteasome degradation. 963 25

The in vitro differentiation of Trypanosoma brucei from bloodstream to procyclic (insect) forms is accompanied by diminishing variant surface glycoprotein (VSG) and increasing levels of procyclin and phosphoenolpyruvate carboxykinase (PEPCK). In this study, we examined the fate of several glycolytic enzymes of T. brucei during differentiation. We observed a down-regulation of glycosomal phosphoglycerate kinase (gPGK) during differentiation. In contrast, intracellular levels of glycosomal glyceraldehyde-3-phosphate dehydrogenase (gGAPDH), aldolase (ALD), and phosphoglucoisomerase (PGI) remained unchanged during differentiation and apparently continued to be synthesized in the procyclic form. To determine the potential role of proteasomes and other proteases during the differentiation process, we tested the effect of lactacystin, a specific inhibitor of proteasome activity, and morpholinourea-Phe-homoPhe-benz-alpha-pyrone (P27), a selective inhibitor of cysteine proteases, on the in vitro differentiation of T. brucei. Cells differentiated normally in the presence of 1 microM lactacystin, which confirmed our previous observation that this differentiation does not require crossing any phase boundaries in the cell cycle (Mutomba and Wang, Mol Biochem Parasitol 1996;80:89-102). But the cells thus differentiated did not increase in number and retained gPGK. Cells differentiated under 2 microM P27 also proceeded at a normal rate but failed to multiply and retained gPGK. However, most of the differentiated cells under 2 microM P27 also retained VSG on the cell membrane surface and expressed higher levels of procyclin suggesting that a cysteine protease(s) may be involved in releasing VSG and partially reducing procyclin during differentiation. This cysteine protease(s) has been tentatively identified in the procyclic cells as a 48 kDa protein through labeling of cysteine protease(s) with a biotinylated P27 homolog K02 (morpholinourea-Phe-homoPhe-vinylsulfone).
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PMID:The role of proteolysis during differentiation of Trypanosoma brucei from the bloodstream to the procyclic form. 966 24

Cytosolic proteinases carry out a variety of regulatory functions by controlling protein levels and/or activities within cells. Calcium-dependent and ubiquitin/proteasome-dependent pathways are common to all eukaryotes. The former pathway consists of a diverse group of Ca(2+)-dependent cysteine proteinases (CDPs; calpains in vertebrate tissues). The latter pathway is highly conserved and consists of ubiquitin, ubiquitin-conjugating enzymes, deubiquitinases, and the proteasome. This review summarizes the biochemical properties and genetics of invertebrate CDPs and proteasomes and their roles in programmed cell death, stress responses (heat shock and anoxia), skeletal muscle atrophy, gametogenesis and fertilization, development and pattern formation, cell-cell recognition, signal transduction and learning, and photoreceptor light adaptation. These pathways carry out bulk protein degradation in the programmed death of the intersegmental and flight muscles of insects and of individuals in a colonial ascidian; molt-induced atrophy of crustacean claw muscle; and responses of brine shrimp, mussels, and insects to environmental stress. Selective proteolysis occurs in response to specific signals, such as in modulating protein kinase A activity in sea hare and fruit fly associated with learning; gametogenesis, differentiation, and development in sponge, echinoderms, nematode, ascidian, and insects; and in light adaptation of photoreceptors in the eyes of squid, insects, and crustaceans. Proteolytic activities and specificities are regulated through proteinase gene expression (CDP isozymes and proteasomal subunits), allosteric regulators, and posttranslational modifications, as well as through specific targeting of protein substrates by a diverse assemblage of ubiquitin-conjugases and deubiquitinases. Thus, the regulation of intracellular proteolysis approaches the complexity and versatility of transcriptional and translational mechanisms.
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PMID:Intracellular proteinases of invertebrates: calcium-dependent and proteasome/ubiquitin-dependent systems. 969 13

We have recently shown that the endoplasmic reticulum (ER) membrane protein, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, is cleaved in isolated membrane fractions enriched for endoplasmic reticulum. Importantly, the cleavage rate is accelerated when the membranes are prepared from cells that have been pretreated with mevalonate or sterols, physiological regulators of the degradation process in vivo (McGee, T. P., Cheng, H. H., Kumagai, H., Omura, S., and Simoni, R. D. (1996) J. Biol. Chem. 271, 25630-25638). In the current study, we further characterize this in vitro cleavage of HMG-CoA reductase. E64, a specific inhibitor of cysteine-proteases, inhibits HMG-CoA reductase cleavage in vitro. In contrast, lactacystin, an inhibitor of the proteasome, inhibits HMG-CoA reductase degradation in vivo but does not inhibit the in vitro cleavage. Purified ER fractions contain lactacystin-sensitive and E64-insensitive proteasome activity as measured by succinyl-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin hydrolysis. We removed the proteasome from purified ER fractions by solubilization with heptylthioglucoside and observed that the detergent extracted, proteasome-depleted membrane fractions retain regulated cleavage of HMG-CoA reductase. This indicates that ER-associated proteasome is not involved in degradation of HMG-CoA reductase in vitro. In order to determine the site(s) of proteolysis of HMG-CoA reductase in vitro, four antisera were prepared against peptide sequences representing various domains of HMG-CoA reductase and used for detection of proteolytic intermediates. The sizes and antibody reactivity of the intermediates suggest that HMG-CoA reductase is cleaved in the in vitro degradation system near the span 8 membrane region, which links the N-terminal membrane domain to the C-terminal catalytic domain of the protein. We conclude that HMG-CoA reductase can be cleaved in the membrane-span 8 region by a cysteine protease(s) tightly associated with ER membranes.
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PMID:Degradation of HMG-CoA reductase in vitro. Cleavage in the membrane domain by a membrane-bound cysteine protease. 970 46

To determine whether proteasome activity is required for tracheary element (TE) differentiation, the proteasome inhibitors clasto-lactacystin beta-lactone and carbobenzoxy-leucinyl-leucinyl-leucinal (LLL) were used in a zinnia (Zinnia elegans) mesophyll cell culture system. The addition of proteasome inhibitors at the time of culture initiation prevented differentiation otherwise detectable at 96 h. Inhibition of the proteasome at 48 h, after cellular commitment to differentiation, did not alter the final percentage of TEs compared with controls. However, proteasome inhibition at 48 h delayed the differentiation process by approximately 24 h, as indicated by examination of both morphological markers and the expression of putative autolytic proteases. These results indicate that proteasome function is required both for induction of TE differentiation and for progression of the TE program in committed cells. Treatment at 48 h with LLL but not clasto-lactacystin beta-lactone resulted in partial uncoupling of autolysis from differentiation. Results from gel analysis of protease activity suggested that the observed incomplete autolysis was due to the ability of LLL to inhibit TE cysteine proteases.
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PMID:Proteasome inhibitors prevent tracheary element differentiation in zinnia mesophyll cell cultures 976 27

Palmitoylation of cysteine residue 34 within the 67-amino acid cytoplasmic domain of the 46-kDa mannose 6-phosphate receptor (MPR 46), which may be anchored to the lipid bilayer, prevents the receptor from entering lysosomes (Schweizer, A., Kornfeld, S., and Rohrer, J. (1996) J. Cell Biol. 132, 577-584). In the present study, we examined the importance of the spacing between the transmembrane domain and the palmitoylation anchor site in the cytoplasmic domain for stability and trafficking of MPR 46. MPR 46 mutants with deletions of residues 20-23 and 24-29 expressed in baby hamster kidney cells were rapidly degraded with half-lives of less than 10 h. The replacement of residues 24-29 by alanine resulted in prolongation of receptor stability (t(1)/(2) approximately 20 h). Whereas mutant MPR 46 could not be detected in lysosomal fractions and inhibitors of lysosomal proteases failed to prevent degradation, treatment with the proteasome inhibitor lactacystin resulted in increased stability of mutant MPR 46. Pulse-chase experiments at low temperature and the acquirement of endoglucosaminidase H-resistant oligosaccharides indicate that the majority of mutant MPR 46 is degraded after leaving the Golgi compartment. Altered trafficking of mutant MPR 46 may be the result of decreased palmitoylation reaching 40% of wild type receptors. The data suggest that the spacing between the transmembrane domain and the proposed palmitoylation anchor site in the cytoplasmic domain of MPR 46 is important for a post Golgi sorting step preventing receptor degradation by multiple proteolytic systems including the proteasome.
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PMID:Stabilization of mutant 46-kDa mannose 6-phosphate receptors by proteasomal inhibitor lactacystin. 983 96

The average polymorphonuclear neutrophil (PMN) lives only a day and then dies by apoptosis. We previously found that the calcium-dependent protease calpain is required for apoptosis in several mouse models of cell death. Here we identify calpain, and its endogenous inhibitor calpastatin, as regulators of human neutrophil apoptosis. Cell death triggered by the translation inhibitor cycloheximide is calpain-dependent, as evidenced using either a calpain active site inhibitor (N-acetyl-leucyl-leucyl-norleucinal) or agents that target calpain's calcium binding sites (PD150606, PD151746). No significant effect on cycloheximide-triggered apoptosis was found by using inhibitors of the proteasome or of other papain-like cysteine proteases, providing further evidence that the active site calpain inhibitor prevents apoptosis via its action on calpain. In addition, we find that potentiation of calpain activity by depleting its endogenous inhibitor, calpastatin, is sufficient to cause apoptosis of neutrophils. Nevertheless, apoptosis signalled via the Fas antigen proceeds regardless of the presence of calpain inhibitor. These experiments support a growing body of work, indicating an upstream regulatory role for calpain in many, but not all, forms of apoptotic cell death. They also identify calpastatin as a participant in apoptotic cell death and suggest that for at least one cell type, a decrease in calpastatin is a sufficient stimulus to initiate calpain-dependent apoptosis.
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PMID:Calpain and calpastatin regulate neutrophil apoptosis. 998 77

Although in the past protein stability commonly has been considered an inherent property of a given protein, the truth is far more complex. Elaborate enzymatic systems exist in multiple intracellular compartments to hydrolyze proteins. These systems are capable of providing a sensitive mechanism to regulate protein expression, a mechanism that is complementary to the transcriptional and translational control mechanisms that influence protein synthesis. The power of regulated proteolysis has been well-demonstrated in the abrupt degradation of cyclins that underlies eukaryotic cell cycle progression. Coincidental with the recent rapid gains in understanding proteolysis at a biochemical level, several human diseases have been found to result from disordered proteolysis. This article reviews several examples of human disease resulting from mutations of genes encoding serine proteases, cysteine proteases, and their inhibitors. Examples are also presented of human diseases resulting from disorders in the highly intricate ubiquitin-proteasome pathway of protein degradation. It is certain that many more human diseases will be associated in the future with disorders of proteolysis.
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PMID:Human genetic diseases of proteolysis. 1009 66


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