Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have isolated a mutant, mts2, in the fission yeast Schizosaccharomyces pombe which is defective in chromosome segregation. The predicted amino-acid sequence of the cloned mts2+ gene product is 75% identical to the S4 subunit of the human 26S ATP/ubiquitin-dependent protease. The human S4 subunit complementary DNA expressed from an S. pombe expression plasmid can rescue an S. pombe mts2 gene disruption. Both observations demonstrate that the mts2+ gene is the S. pombe homologue of the human S4 subunit. In addition, we provide genetic evidence for a physical interaction between the S4 and the related S7 subunit in the 26S multiprotein protease. We show that polyubiquitin-conjugated proteins accumulate in the mts2 mutant at the restrictive temperature, demonstrating that the mutant has an in vivo defect in the ubiquitin-dependent proteolysis pathway. Finally, the phenotype for the mts2 mutant indicates that protein degradation by the 26S protease is essential not for entry into but for the completion of mitosis.
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PMID:Defective mitosis due to a mutation in the gene for a fission yeast 26S protease subunit. 824 31

Ubiquitin is a highly conserved polypeptide found in all eukaryotes. The major function of ubiquitin is to target proteins for complete or partial degradation by a multisubunit protein complex called the proteasome. Here, the Drosophila fat facets gene, which is required for the appropriate determination of particular cells in the fly eye, was shown to encode a ubiquitin-specific protease (Ubp), an enzyme that cleaves ubiquitin from ubiquitin-protein conjugates. The Fat facets protein (FAF) acts as a regulatory Ubp that prevents degradation of its substrate by the proteasome. Flies bearing fat facets gene mutations were used to show that a Ubp is cell type--and substrate-specific and a regulator of cell fate decisions in a multicellular organism.
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PMID:Control of cell fate by a deubiquitinating enzyme encoded by the fat facets gene. 852 78

The platelet-derived growth factor beta-receptor undergoes polyubiquitination as a consequence of ligand binding. Ubiquitin conjugation to protein is implicated in proteasome-dependent proteolytic pathway for short-lived proteins. In the present study, we have examined effects of different kinds of cell-penetrating proteasome inhibitors, including N-benzyloxycarbonyl-L-isoleucyl-gamma-t-butyl-L-glutamyl-L-alanyl-L-l eucinal (PSI) and a Streptomyces metabolite lactacystin, on ligand-stimulated degradation of the beta-receptor. These proteasome inhibitors were found to considerably inhibit the degradation of autophosphorylated and polyubiquitinated receptors, suggesting the possible involvement of proteasomes in the degradation process of the ligand-activated beta-receptor.
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PMID:Ligand-activated platelet-derived growth factor beta-receptor is degraded through proteasome-dependent proteolytic pathway. 852 15

The claw muscles of decapod crustaceans undergo a molt-induced atrophy to facilitate withdrawal of the claws at ecdysis. Polyubiquitin expression, as well as the levels of ubiquitin conjugates, a ubiquitin-conjugating enzyme involved in the ATP/ubiquitin-dependent proteolytic pathway (crustacean E2(16 kDa) homolog of Drosophila UbcD1), and proteasome, were examined to determine the role of ATP/ubiquitin-dependent proteolysis in the enhanced degradation of myofibrillar proteins during muscle atrophy. A partial-length clone (1.7 kb) of polyubiquitin was isolated from a lobster muscle cDNA library; the 5' end lacked the 5' untranslated region (UTR) and the beginning of the first ubiquitin monomer, while the 3' end contained the terminal ubiquitin monomer and 3' UTR. The deduced amino acid sequence was 100% identical with that from Manduca, Drosophila, and human. In land crab claw muscle, the polyubiquitin mRNA (2.7 kb) increased about 5-fold and ubiquitin-protein conjugates (> 200 kDa) increased about 8-fold during atrophy. In contrast, the level of a ubiquitin-conjugating enzyme (E2(16 kDa)) remained unchanged. The proteasome, which constitutes the catalytic core of the ATP/ubiquitin-dependent proteinase complex, increased about 2-fold during proecdysis, reaching its highest level immediately before ecdysis. These results suggest that the ATP/ubiquitin-dependent proteolytic pathway contributes to the changes in protein metabolism that occur during molt-induced muscle atrophy.
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PMID:Polyubiquitin in crustacean striated muscle: increased expression and conjugation during molt-induced claw muscle atrophy. 854 19

Ubiquitin conjugation is a signal for degradation of eukaryotic proteins by the 26S protease. Conjugation of a homopolymeric multiubiquitin chain to a substrate lysine residue results in 10-fold faster degradation than does conjugation of monoubiquitin, but the molecular basis of enhanced targeting by chains is unknown. We show that ubiquitin residues L8, I44, and V70 are critical for targeting. Mutation of pairs of these residues to alanine had little effect on attachment of ubiquitin to substrates but severely inhibited degradation of the resulting conjugates. The same mutations blocked the binding of chains to a specific subunit (S5a) of the regulatory complex of the 26S protease. The side chains implicated in this binding--L8, I44, and V70--form repeating patches on the chain surface. Thus, hydrophobic interactions between these patches and S5a apparently contribute to enhanced proteolytic targeting by multiubiquitin chains.
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PMID:Surface hydrophobic residues of multiubiquitin chains essential for proteolytic targeting. 857 Jun 49

Ubiquitin-dependent proteolysis is required for cell cycle progression. Here, we demonstrate that the proteasome is activated during in vivo Xenopus egg activation, induced by treatment with the calcium ionophore A23187. It was found that activation is due to the calcium-induced assembly of the 26 S proteasome from the 20 S proteasome. We propose that proteasome activation is regulated by cell cycle calcium transients, which are controlled upstream by an endogenous cell cycle oscillator that is independent of the cyclin-dependent kinase cycle.
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PMID:Activation of the proteasome during Xenopus egg activation implies a link between proteasome activation and intracellular calcium release. 857 36

Lewy bodies (LBs) are the pathological hallmarks of degenerating neurons in the brains of patients with Parkinson's disease and diffuse Lewy body disease. We developed a novel purification procedure for LBs using sucrose density separation followed by fluorescence-activated particle sorting, and we raised > 15 monoclonal antibodies to LBs purified from diffuse Lewy body disease brains. The monoclonal antibody that stained the largest number of LBs most intensely did not recognize ubiquitin in free or monoubiquitinated forms nor the ubiquitin conjugating enzymes, but it did react with polyubiquitin chains as well as with high molecular weight polyubiquitinated LB-derived proteins. Thus, these results suggest that LBs contain polyubiquitin chains. Although polyubiquitination of LB proteins may trigger ubiquitin-proteasome proteolytic pathways, the incomplete activation of these pathways could play a mechanistic role in the formation of LBs in neurodegenerative diseases.
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PMID:Purification and characterization of Lewy bodies from the brains of patients with diffuse Lewy body disease. 862 21

Covalent conjugation of ubiquitin to intracellular proteins is a signal for degradation by the 26S protease. Conjugation is usually accomplished by the sequential action of activating (E1), conjugating (E2), and ligase (E3) enzymes. Each of these enzymes forms a covalent thiol ester with ubiquitin as part of its catalytic cycle. In most cases, the apparent role of the ubiquitin conjugating enzyme (E2) is to transfer ubiquitin from the E1 active site to the E3 active site. Ubiquitin is then delivered from E3 to the substrate lysine residue. An unusually large, reticulocyte-specific enzyme, known as E2-230K, is unique among the large family of E2 enzymes is being susceptible to inhibition by inorganic arsenite [Klemperer et al. (1989) Biochemistry 28, 6035-6041]. We show that phenylarsenoxides potently inhibit E2-230K, apparently by binding to vicinal Cys residues of the enzyme: bound aminophenylarsenoxide partially protects the enzyme against inactivation by N-ethylmalemide (NEM), and prior enzyme inactivation with NEM blocks enzyme binding to immobilized phenylarsenoxide. Studies on the mechanistic basis of inhibition showed that a concentration of (aminophenyl)arsenoxide that produced complete inhibition of steady-state turnover had no effect on the turnover of the preformed E2-ubiquitin adduct. However, when the enzyme was preincubated with this concentration of inhibitor prior to initiation of adduct formation, the level of E2-associated ubiquitin was reduced by 60%. These results are consistent with a model in which two Cys residues of the enzyme sequentially form thiol esters with ubiquitin and the second of these Cys residues is bound to arsenic in the enzyme-inhibitor complex. In this model, E2-230K functions as an E2-E3 hybrid.
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PMID:Mechanism of ubiquitin conjugating enzyme E2-230K: catalysis involving a thiol relay? 863 98

ATP-dependent proteolysis of 125I-labeled human alpha-globin, bovine alpha-lactalbumin, bovine serum albumin, or chicken lysozyme was assessed in a rabbit reticulocyte extract supplemented with ATP, excess ubiquitin, and variable amounts of ubiquitin aldehyde (Ubal), an inhibitor of many ubiquitin-protein isopeptidases. Low concentrations (0.8 microM) of Ubal increased the ATP-dependent degradation of 125I-alpha-globin by approximately 30% after 2 h at 37 degrees C, had little effect on 125I-lysozyme turnover, and decreased 125I-alpha-lactalbumin or 125I-albumin degradation by approximately 20%. The ATP-dependent degradation of all substrates was inhibited by high concentrations (> 3 microM) of Ubal throughout the incubation (15 min to 2 h); after 2 h, this inhibition ranged from 15% for 125I-alpha-globin to approximately 85% for 125I-alpha-lactalbumin and 125I-albumin. Levels of ubiquitin-125I-protein conjugates were increased significantly with Ubal; with > or = 8.0 microM Ubal, high molecular mass multiubiquitinated conjugates were particularly evident for 125I-alpha-globin and 125I-alpha-lactalbumin. These mixtures also accumulated ubiquitin conjugates with sizes expected for di- through pentaubiquitin oligomers. The results are consistent with the following proposed events: The ATP-dependent degradation of 125I-alpha-lactalbumin or 125I-albumin is probably mediated almost exclusively through polyubiquitinated intermediates. High Ubal concentrations inhibit an isopeptidase(s) which normally disassembles "unanchored" polyubiquitin chains that remain after substrate degradation by the 26S proteasome; these chains accumulate to inhibit further conjugate degradation. Much of the ATP-dependent degradation of 125I-alpha-globin and, to a lesser degree, 125I-lysozyme may occur through alternative structures where ubiquitin monomers or short oligomers are ligated to one or more substrate lysines. For 125I-alpha-globin, even low concentrations of Ubal effectively inhibit deubiquitination of these conjugates to enhance alpha-globin degradation.
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PMID:Differential effects of ubiquitin aldehyde on ubiquitin and ATP-dependent protein degradation. 871 81

A dominant insertional P-element mutation enhances position-effect variegation in Drosophila melanogaster. The mutation is homozygous, viable, and fertile and maps at 64E on the third chromosome. The corresponding gene was cloned by transposon tagging. Insertion of the transposon upstream of the open reading frame correlates with a strong reduction of transcript level. A transgene was constructed with the cDNA and found to have the effect opposite from that of the mutation, namely, to suppress variegation. Sequencing of the cDNA reveals a large open reading frame encoding a putative ubiquitin-specific protease (Ubp). Ubiquitin marks various proteins, frequently for proteasome-dependent degradation. Ubps can cleave the ubiquitin part from these proteins. We discuss the link established here between a deubiquitinating enzyme and epigenetic silencing processes.
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PMID:The dose of a putative ubiquitin-specific protease affects position-effect variegation in Drosophila melanogaster. 881 85


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