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 ubiquitin-proteasome system (UPS) is critical for specific degradation of cellular proteins and plays a pivotal role on protein breakdown in muscle atrophy. Here, we show that ZNF216 directly binds polyubiquitin chains through its N-terminal A20-type zinc-finger domain and associates with the 26S proteasome. ZNF216 was colocalized with the aggresome, which contains ubiquitinylated proteins and other UPS components. Expression of Znf216 was increased in both denervation- and fasting-induced muscle atrophy and upregulated by expression of constitutively active FOXO, a master regulator of muscle atrophy. Mice deficient in Znf216 exhibited resistance to denervation-induced atrophy, and ubiquitinylated proteins markedly accumulated in neurectomized muscle compared to wild-type mice. These data suggest that ZNF216 functions in protein degradation via the UPS and plays a crucial role in muscle atrophy.
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PMID:A novel ubiquitin-binding protein ZNF216 functioning in muscle atrophy. 1642 5

In the present study, we report the identification and characterization of MEX (MEKK1-related protein X), a protein with homology to MEKK1 that is expressed uniquely in the testis. MEX is comprises four putative zinc-binding domains including an N-terminal SWIM (SWI2/SNF2 and MuDR) domain of unknown function and two RING (really interesting new gene) fingers separated by a ZZ zinc finger domain. Biochemical analyses revealed that MEX is self-ubiquitinated and targeted for degradation through the proteasome pathway. MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin. The enhancement of apoptosis by MEX required a functional SWIM domain, suggesting that MEX ubiquitination is critical for the enhancement of apoptosis. These results indicate that MEX acts as an E3 Ub ligase, an activity that is dependent on the SWIM domain and suggest a role for MEX in the regulation of death receptor-induced apoptosis in the testes.
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PMID:MEX is a testis-specific E3 ubiquitin ligase that promotes death receptor-induced apoptosis. 1652 93

Ubiquitin ligases play an important regulatory role in the control of protein degradation processes via the ubiquitin/26S proteasome pathway in eukaryotes. These enzymes participate in substrate specification and mediate the transfer of ubiquitin to target proteins. A large number of ubiquitin ligases are predicted in the eukaryotes whose genomes have been sequenced; in Arabidopsis thaliana more than 1300 genes are thought to encode ubiquitin ligases. At least three classes of ubiquitin ligases are present in Arabidopsis, one of which comprises about 470 RING zinc-finger domain proteins. Within this class we have characterized the ATL family that encodes a RING-H2 finger. We identified 80 members of this family in A. thaliana and 121 in Oryza sativa. About 60% of the rice ATLs are clustered with A. thaliana ATLs, and in many cases the gene products showed sequence similarities beyond the ATL's conserved features, suggesting that they could be orthologous genes. Ninety percent of the ATLs are intronless genes, suggesting that the structure of the basic ATL protein may have evolved as a functional module. We carried out a survey of T-DNA insertions in 30% of the Arabidopsis ATL genes and screened for possible phenotypes. Four of these genes are likely to be essential for viability, since homozygous plants for the T-DNA insertion were not recovered. One of them, ATL8, is mainly expressed in young siliques, suggesting a role during embryogenesis. We also recovered a line carrying a T-DNA insertion in ATL43 that showed an ABA-insensitive phenotype, suggesting a role of this gene in the ABA response. The organization of ATLs in Arabidopsis and rice in this study will be a valuable comprehensive guide for this multigene family.
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PMID:The ATL gene family from Arabidopsis thaliana and Oryza sativa comprises a large number of putative ubiquitin ligases of the RING-H2 type. 1655 37

The proteasome is a multisubunit complex with a central role in non-lysosomal proteolysis and the processing of proteins for presentation by the MHC class I pathway. The 16kDa proteasome maturation protein POMP (also named proteassemblin or hUmp1) acts as a chaperone and is essential for the maturation of the 20S proteasome proteolytic core complex. However, the exact mechanism, timing and localisation of mammalian proteasome assembly remains elusive. We sought to investigate the localisation of POMP within the cell and therefore purified the protein and produced a polyclonal antibody. For immunisation, POMP was overexpressed and purified from a bacterial GST-system. Interestingly, after removal of the GST-tag, POMP was hardly detectable by Coomassie blue- and Ponceau red-staining. However, with a reverse zinc-staining, the protein could easily be visualised. POMP was gel-filtrated and eluted from a calibrated chromatography column with an apparent molecular weight of approximately 64kDa, suggesting that it forms tetramers. Moreover, localisation studies by immunofluorescence stainings and confocal microscopy revealed that POMP is present in the cytoplasm as well as in the nucleus.
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PMID:Possible tetramerisation of the proteasome maturation factor POMP/proteassemblin/hUmp1 and its subcellular localisation. 1662 3

Zinc transporters play important roles in a wide range of biochemical processes. Here we report an important function of ZnT5/ZnT6 hetero-oligomeric complexes in the secretory pathway. The activity of human tissue-nonspecific alkaline phosphatase (ALP) expressed in ZnT5(-)ZnT7(-/-) cells was significantly reduced compared with that expressed in wild-type cells as in the case of endogenous chicken tissue-nonspecific ALP activity. The inactive human tissue-nonspecific ALP in ZnT5(-)ZnT7(-/-) cells was degraded by proteasome-mediated degradation without being trafficked to the plasma membrane. ZnT5(-)ZnT7(-/-) cells showed exacerbation of the unfolded protein response as did the wild-type cells cultured under a zinc-deficient condition, revealing that both complexes play a role in homeostatic maintenance of secretory pathway function. Furthermore, we showed that expression of ZnT5 mRNA was up-regulated by the endoplasmic reticulum stress in various cell lines. The up-regulation of the hZnT5 transcript was mediated by transcription factor XBP1 through the TGACGTGG sequence in the hZnT5 promoter, and this sequence was highly conserved in the ZnT5 genes of mouse and chicken. These results suggest that zinc transport into the secretory pathway is strictly regulated for the homeostatic maintenance of secretory pathway function in vertebrate cells.
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PMID:Zinc transport complexes contribute to the homeostatic maintenance of secretory pathway function in vertebrate cells. 1663 52

Eukaryotic MPN domain proteins are components of the complexes proteasome lid, COP9-signalosome (CSN), and translation initiation factor 3 (eIF3). The proteasome lid Rpn11 and COP9-signalosome Csn5 subunits, which contain the conserved JAMM motif involved in zinc ion coordination, show catalytic isopeptidase activity. Homology modeling indicates that the MPN domain of Mov34 cannot coordinate a zinc ion in the same manner as catalytically active MPN domains. In this work, we show that the MPN domain of Mov34 is highly resistant to proteolysis and the major product comprises residues 9-186, which includes the conserved MPN domain. Two clones containing the MPN domain region (MPN1-177 and MPN1-186) including the eight N-terminal residues show a less pronounced band in the 220 nm region of the CD, indicating lower alpha-helical content relative to the clones lacking these residues (MPN9-177 and MPN9-186). However, clones lacking residues 1-8 show lower expression levels and thermal stability, indicating that residues 1-8 are required for proper folding and stability of this particular MPN domain.
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PMID:Characterization of the human ortholog of Mov34 reveals eight N-terminal residues important for MPN domain stability. 1684 55

Peptide:N-glycanase has been thought to be responsible for proteasome-dependent degradation of misfolded glycoproteins translocated from the endoplasmic reticulum (ER) to the cytosol. Therefore, the enzyme was supposed to be able to distinguish between native and non-native glycoproteins. In the present study, a recombinant, yeast peptide:N-glycanase, Png1p, was expressed in Escherichia coli as inclusion bodies and was purified, refolded and characterized. The results showed that the recombinant enzyme has a broad pH range adaptation, from pH 4.0 to pH 10.0, and has an optimum temperature of 30 degrees C. This enzyme is a zinc metalloenzyme. Its activity was abolished with the addition of EDTA and not restored by adding metal ions. Furthermore, the deglycosylation efficiency of recombinant Png1p from E. coli was investigated with respect to the substrate conformation in vitro. When ribonuclease B (RNase B) was denatured at 60-65 degrees C or by 40-60 mM dithiothreitol, indicated by its obvious structural change and sharpest activity change, its deglycosylation by Png1p was most prominent. The deglycosylation efficiency of RNase B by Png1p was found to be related to its structural conformation and enzymatic activity.
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PMID:Influence of substrate conformation on the deglycosylation of ribonuclease B by recombinant yeast peptide:N-glycanase. 1721 53

The ICP0 protein (bICP0) encoded by bovine herpesvirus 1 is the major viral regulatory protein because it stimulates all viral promoters and, consequently, productive infection. Like other ICP0 analogues encoded by Alphaherpesvirinae subfamily members, bICP0 contains a zinc RING finger near its amino terminus that is necessary for activating transcription, regulating subcellular localization, and inhibiting interferon-dependent transcription. In this study, we discovered that sequences near the C terminus, and the zinc RING finger, are necessary for inhibiting the human beta interferon (IFN-beta) promoter. In contrast to herpes simplex virus type 1-encoded ICP0, bICP0 reduces interferon response factor 3 (IRF3), but not IRF7, protein levels in transiently transfected cells. The zinc RING finger and sequences near the C terminus are necessary for bICP0-induced degradation of IRF3. A proteasome inhibitor, lactacystin, interfered with bICP0-induced degradation of IRF3, suggesting that bICP0, directly or indirectly, targets IRF3 for proteasome-dependent degradation. IRF3, but not IRF7, is not readily detectable in the nuclei of productively infected bovine cells during the late stages of infection. In the context of productive infection, IRF3 and IRF7 are detected in the nucleus at early times after infection. At late times after infection, IRF7, but not IRF3, is still detectable in the nuclei of infected cells. Collectively, these studies suggest that the ability of bICP0 to reduce IRF3 protein levels is important with respect to disarming the IFN response during productive infection.
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PMID:The infected cell protein 0 encoded by bovine herpesvirus 1 (bICP0) induces degradation of interferon response factor 3 and, consequently, inhibits beta interferon promoter activity. 1721 77

Poh1 deubiquitinase activity is required for proteolytic processing of polyubiquitinated substrates by the 26S proteasome, linking deubiquitination to complete substrate degradation. Poh1 RNA interference (RNAi) in HeLa cells resulted in a reduction in cell viability and an increase in polyubiquitinated protein levels, supporting the link between Poh1 and the ubiquitin proteasome pathway. To more specifically test for any requirement of the zinc metalloproteinase motif of Poh1 to support cell viability and proteasome function, we developed a RNAi complementation strategy. Effects on cell viability and proteasome activity were assessed in cells with RNAi of endogenous Poh1 and induced expression of wild-type Poh1 or a mutant form of Poh1, in which two conserved histidines of the proposed catalytic site were replaced with alanines. We show that an intact zinc metalloproteinase motif is essential for cell viability and 26S proteasome function. As a required enzymatic component of the proteasome, Poh1 is an intriguing therapeutic drug target for cancer.
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PMID:The JAMM motif of human deubiquitinase Poh1 is essential for cell viability. 1723 85

Interferon regulatory factor 3 (IRF3) is a key transcription factor involved in the induction of interferon (IFN) in response to viral infection. Rotavirus non-structural protein NSP1 binds to and targets IRF3 for proteasome degradation early post-infection. Mutational analysis of cysteine and histidine residues within the conserved N-terminal zinc-binding domain in NSP1 of bovine rotavirus strain B641 abolished IRF3 degradation in transfected cells. Thus, the integrity of the zinc-binding domain in NSP1 is important for degradation of IRF3. In contrast to bovine strain B641, IRF3 was stable in cells infected with porcine rotavirus strain OSU and OSU NSP1 bound only weakly to IRF3. Both B641 NSP1 and OSU NSP1 were stabilized in cells or cell-free extracts in the presence of the proteasome inhibitor MG132 and when the zinc-binding domain was disrupted by site-directed mutagenesis. Data from the B641 analyses that show IRF3 degradation is dependent on the presence of NSP1 and the integrity of the N-terminal zinc-binding domain, coupled with the regulated stability of IRF3 and NSP1 by the proteasome, collectively support the hypothesis that NSP1 is an E3 ubiquitin ligase.
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PMID:Zinc-binding domain of rotavirus NSP1 is required for proteasome-dependent degradation of IRF3 and autoregulatory NSP1 stability. 1725 80


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