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)

The effect of oxidative stress induced by neurotoxic metal ions on the properties of the brain 20S proteasome or multicatalytic proteinase complex (MPC) has been studied. Exposure of the 20S proteasome to increasing amounts of Fe(III), Fe(II), Cu(II) or Zn(II) affects its main hydrolytic activities: trypsin-like (T-L), chymotrypsin-like (ChT-L), peptidylglutamyl-peptide hydrolase (PGPH), branched-chain amino acid preferring (BrAAP) and caseinolytic activities, although in different ways. T-L activity showed gradual activation by both iron ions but inhibition by Cu(II) and Zn(II). ChT-L and PGPH activities were inhibited whereas BrAAP activity was widely activated by all the tested metal salts except for zinc ions. Moreover, the exposure to ferrous salt increased the degradation rate of casein. The functional effects appear to be linked to oxidation-induced modifications, as demonstrated by an increase of carbonyl groups following the exposure to metal ions. In addition, modifications induced by ferrous salt on the catalytic subunits were also supported by western blot analyses performed using anti-X, anti-Y and anti-Z antibodies. The results obtained clearly indicate that metal-catalyzed oxidation strongly affects the functions of the brain 20S proteasome, even though the catalytic subunits seem to be differently influenced by oxidative phenomena.
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PMID:Effect of neurotoxic metal ions on the proteolytic activities of the 20S proteasome from bovine brain. 1220 11

Mdm2 and MdmX function as cellular regulators of the p53 tumor suppressor protein. Mdm2, a p53 inducible protein, negatively regulates p53 by inhibiting p53 transcriptional activity and promoting ubiquitin mediated proteasome degradation. The Mdm2 ring finger domain has been shown to possess E3 ligase activity and to be a necessary domain for targeting p53 degradation. MdmX, a p53 binding protein sharing a high degree of structural homology with Mdm2, has emerged as another negative regulator of the p53 tumor suppressor. MdmX has also been shown to block p53 transactivation but unlike Mdm2 cannot induce p53 degradation. Since MdmX also possesses a ring finger domain that allows MdmX to associate with Mdm2, this study focused on elucidating how the ring and zinc fingers of these two proteins affected p53 function. We have generated a series of fusion proteins between Mdm2 and MdmX by swapping the ring finger domains with or without the zinc finger domains and examined how these fusions regulated p53 induced transactivation, ubiquitination, and degradation. All fusions inhibited the transcriptional activity of p53. In the absence of Mdm2, none of the fusion proteins could trigger p53 ubiquitination or degradation. However, in a cell line with endogenous Hdm2, Mdm2:X fusions containing the ring finger domain with or without the zinc finger domain demonstrated p53 ubiquitination presumably through stabilization of Hdm2. Additionally, an Mdm2:XZFRF fusion also degraded p53 when endogenous Hdm2 was present. Results from immunofluorescence studies suggest that p53 is colocalized to the cytoplasm when coexpressed with a Mdm2:X fusion (Mdm2:XZFRF) and that this fusion is capable of stabilizing endogenous Hdm2. Since none of the fusions triggered p53 ubiquitination in cells lacking Mdm2, these results indicate that the E3 ligase domain within the ring finger of Mdm2 when part of MdmX and the MdmX ring finger fused to Mdm2 were not sufficient to trigger p53 ubiquitination, in vivo.
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PMID:Overexpression of Mdm2 and MdmX fusion proteins alters p53 mediated transactivation, ubiquitination, and degradation. 1260 Jan 96

The tumor suppressor PTEN is a putative negative regulator of the phosphatidylinositol 3-kinase/Akt pathway. Exposure to Zn2+ ions induces Akt activation, suggesting that PTEN may be modulated in this process. Therefore, the effects of Zn2+ on PTEN were studied in human airway epithelial cells and rat lungs. Treatment with Zn2+ resulted in a significant reduction in levels of PTEN protein in a dose- and time-dependent fashion in a human airway epithelial cell line. This effect of Zn2+was also observed in normal human airway epithelial cells in primary culture and in rat airway epithelium in vivo. Concomitantly, levels of PTEN mRNA were also significantly reduced by Zn2+ exposure. PTEN phosphatase activity evaluated by measuring Akt phosphorylation decreased after Zn2+ treatment. Pretreatment of the cells with a proteasome inhibitor significantly blocked zinc-induced reduction of PTEN protein as well as the increase in Akt phosphorylation, implicating the involvement of proteasome-mediated PTEN degradation. Further study revealed that Zn2+-induced ubiquitination of PTEN protein may mediate this process. A phosphatidylinositol 3-kinase inhibitor blocked PTEN degradation induced by Zn2+, suggesting that phosphatidylinositol 3-kinase may participate in the regulation of PTEN. However, both the proteasome inhibitor and phosphatidylinositol 3-kinase inhibitor failed to prevent significant down-regulation of PTEN mRNA expression in response to Zn2+. In summary, exposure to Zn2+ ions causes PTEN degradation and loss of function, which is mediated by an ubiquitin-associated proteolytic process in the airway epithelium.
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PMID:Zinc-induced PTEN protein degradation through the proteasome pathway in human airway epithelial cells. 1274 24

We have isolated an RGS-GAIP interacting protein that links RGS proteins to protein degradation. GIPN (GAIP interacting protein N terminus) is a 38-kDa protein with an N-terminal leucine-rich region, a central RING finger-like domain, and a putative C-terminal transmembrane domain. GIPN binds exclusively to RGS proteins of subfamily A, RGS-GAIP, RGSZ1, and RGSZ2. The N-terminal leucine-rich region of GIPN interacts with the cysteine-rich motif of RGS-GAIP. GIPN mRNA is ubiquitously expressed, and GIPN is found on the plasma membrane of transfected HEK293 cells. Endogenous GIPN is concentrated along the basolateral plasma membrane of proximal and distal tubules in rat kidney, where many G protein-coupled receptors and some G proteins are also located. Two immunoreactive species are found in rat kidney, a 38-kDa cytosolic form and an approximately 94-kDa membrane form. GIPN shows Zn2+- and E1/E2-dependent autoubiquitination in vitro, suggesting that it has E3 ubiquitin ligase activity. Overexpression of GIPN stimulates proteasome-dependent reduction of endogenous G alpha i3 in HEK293 cells and reduces the half-life of overexpressed G alpha i3-YFP. Thus, our findings suggest that GIPN is involved in the degradation of G alpha i3 subunits via the proteasome pathway. RGS-GAIP functions as a bifunctional adaptor that binds to G alpha subunits through its RGS domain and to GIPN through its cysteine string motif.
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PMID:Promotion of G alpha i3 subunit down-regulation by GIPN, a putative E3 ubiquitin ligase that interacts with RGS-GAIP. 1282 7

Herpes simplex virus type 1 regulatory protein ICP0 contains a zinc-binding RING finger and has been shown to induce the proteasome-dependent degradation of a number of cellular proteins in a RING finger-dependent manner during infection. This domain of ICP0 is also required to induce the formation of unanchored polyubiquitin chains in vitro in the presence of ubiquitin-conjugating enzymes UbcH5a and UbcH6. These data indicate that ICP0 has the potential to act as a RING finger ubiquitin ubiquitin-protein isopeptide ligase (E3) and to induce the degradation of certain cellular proteins through ubiquitination and proteasome-mediated degradation. Here we demonstrate that ICP0 is a genuine RING finger ubiquitin E3 ligase that can interact with and mediate the ubiquitination of the major oncoprotein p53 both in vitro and in vivo. Ubiquitination of p53 requires ICP0 to have an intact RING finger domain and occurs independently of its ability to bind to the ubiquitin-specific protease USP7.
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PMID:The herpes simplex virus type 1 (HSV-1) regulatory protein ICP0 interacts with and Ubiquitinates p53. 1285 95

In response to activation of certain cell surface receptors, inositol 1,4,5-trisphosphate receptors (InsP3Rs), which are located in the endoplasmic reticulum, can be rapidly ubiquitinated and then degraded by the proteasome. Ubiquitination is mediated by the concerted action of ubiquitin-conjugating enzymes (Ubcs or E2s) and ubiquitin-protein ligases (E3s). In the present study we have examined the enzymology of ubiquitination of endogenous InsP3Rs in muscarinic agonist-stimulated SH-SY5Y human neuroblastoma cells, focusing our attention on two mammalian E2s, MmUbc6 and MmUbc7, that have been implicated in endoplasmic reticulum-associated degradation (ERAD) and are homologous to the yeast ERAD E2s, Ubc6p and Ubc7p. Analysis of SH-SY5Y cells stably expressing these enzymes and their dominant-negative mutants revealed that MmUbc7 mediates InsP3R ubiquitination and down-regulation, but that MmUbc6 does not. These data indicate that InsP3Rs are processed by a component of the ERAD pathway and suggest that MmUbc7 may be employed selectively to ubiquitinate proteins, like InsP3Rs, that are subject to regulated ERAD. Additional studies showed that the Zn2+ chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine blocked InsP3R ubiquitination, suggesting that a RING finger domain-containing E3 is also involved in this process. Finally, muscarinic agonist-induced InsP3R ubiquitination was seen in rat brain slices, indicating that the results obtained from SH-SY5Y cells reflect a physiological process.
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PMID:Inositol 1,4,5-trisphosphate receptor ubiquitination is mediated by mammalian Ubc7, a component of the endoplasmic reticulum-associated degradation pathway, and is inhibited by chelation of intracellular Zn2+. 1286 71

During the early stages of herpes simplex virus type 1 (HSV-1) infection, viral immediate-early regulatory protein ICP0 localizes to and disrupts cellular nuclear structures known as PML nuclear bodies or ND10. These activities correlate with the functions of ICP0 in stimulating lytic infection and reactivating quiescent HSV-1. The disruption of ND10 occurs because ICP0 induces the loss of the SUMO-1-modified forms of PML and the subsequent proteasome-mediated degradation of the PML protein. The functions of ICP0 are largely dependent on the integrity of its zinc-binding RING finger domain. Many RING finger proteins have been found to act as ubiquitin E3 ligase enzymes, stimulating the production of conjugated polyubiquitin chains in the presence of ubiquitin, the ubiquitin-activating enzyme E1, and the appropriate E2 ubiquitin-conjugating enzyme. Substrate proteins that become polyubiquitinated are then subject to degradation by proteasomes. We have previously shown that purified full-length ICP0 acts as an efficient E3 ligase in vitro, producing high-molecular-weight polyubiquitin chains in a RING finger-dependent but substrate-independent manner. In this paper we report on investigations into the factors governing the degradation of PML induced by ICP0 in a variety of in vivo and in vitro assays. We found that ICP0 expression increases the levels of ubiquitinated PML in transfected cells. However, ICP0 does not interact with or directly ubiquitinate either unmodified PML or SUMO-1-modified PML in vitro, suggesting either that additional factors are required for the ICP0-mediated ubiquitination of PML in vivo or that PML degradation is an indirect consequence of some other activity of ICP0 at ND10. Using a transfection-based approach and a family of deletion and point mutations of PML, we found that efficient ICP0-induced PML degradation requires sequences within the C-terminal part of PML and lysine residue 160, one of the principal targets for SUMO-1 modification of the protein.
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PMID:PML residue lysine 160 is required for the degradation of PML induced by herpes simplex virus type 1 regulatory protein ICP0. 1288 87

Induction of gene expression in response to DNA damage is important for repairing damaged DNA for cell survival. Previously, we identified a novel zinc finger protein, ZBRK1, which contains a KRAB domain at the N terminus, eight zinc fingers at the center, and a BRCA1-binding region at the C terminus. In a BRCA1-dependent manner, ZBRK1 represses Gadd45a transcription through binding to a specific sequence in intron 3. In addition, ZBRK1-binding sequences are located at the regulatory region of many DNA damage-inducible genes, suggesting that ZBRK1 may have a role in DNA damage response. However, it is unclear how transcription repression by ZBRK1 is relieved subsequent to DNA damage. Here we report that ZBRK1 is rapidly degraded upon treatment with the DNA-damaging agents UV and methyl methanesulfonate. Specific proteasome inhibitors block DNA damage-induced degradation of ZBRK1, and the polyubiquitinated form of ZBRK1 is detectable, suggesting that the ubiquitin-proteasome pathway mediates the degradation of ZBRK1. In both BRCA1-proficient and -deficient cells, ZBRK1 is degraded with similar efficiencies independent of BRCA1 E3 ligase activity. By analysis of a series of ZBRK1 mutants, a 44-amino-acid element located between the N-terminal KRAB domain and the eight zinc fingers was found to be sufficient for the DNA damage-induced degradation of ZBRK1. Cells expressing a ZBRK1 mutant lacking the 44-amino-acid element are hypersensitive to DNA damage and are compromised for Gadd45a derepression. These results indicate that ZBRK1 is a novel target for DNA damage-induced degradation and provide a mechanistic explanation of how ZBRK1 is regulated in response to DNA damage.
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PMID:Degradation of transcription repressor ZBRK1 through the ubiquitin-proteasome pathway relieves repression of Gadd45a upon DNA damage. 1451 99

APOBEC3G is a human cellular enzyme that is incorporated into retroviral particles and acts to restrict retroviral replication in infected cells by deaminating dC to dU in the first (minus)-strand cDNA replication intermediate. HIV, however, encodes a protein (virion infectivity factor, Vif ), which overcomes APOBEC3G-mediated restriction but by an unknown mechanism. Here, we show that Vif triggers APOBEC3G degradation by a proteasome-dependent pathway and that an 80 amino acid region of APOBEC3G surrounding its first zinc coordination motif is sufficient to confer the ability to partake in an interaction involving Vif. Inhibitors of this interaction might therefore prove therapeutically useful in blocking Vif-mediated APOBEC3G destruction.
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PMID:The Vif protein of HIV triggers degradation of the human antiretroviral DNA deaminase APOBEC3G. 1461 29

The JAMM (JAB1/MPN/Mov34 metalloenzyme) motif in Rpn11 and Csn5 underlies isopeptidase activities intrinsic to the proteasome and signalosome, respectively. We show here that the archaebacterial protein AfJAMM possesses the key features of a zinc metalloprotease, yet with a distinct fold. The histidine and aspartic acid of the conserved EX(n)HS/THX(7)SXXD motif coordinate a zinc, whereas the glutamic acid hydrogen-bonds an aqua ligand. By analogy to the active site of thermolysin, we predict that the glutamic acid serves as an acid-base catalyst and the second serine stabilizes a tetrahedral intermediate. Mutagenesis of Csn5 confirms these residues are required for Nedd8 isopeptidase activity. The active site-like architecture specified by the JAMM motif motivates structure-based approaches to the study of JAMM domain proteins and the development of therapeutic proteasome and signalosome inhibitors.
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PMID:JAMM: a metalloprotease-like zinc site in the proteasome and signalosome. 1473 82


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