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)

Regulation of the transcription factor NF-kappaB involves proteasome-mediated processing of the NF-kappaB1 p105 precursor protein, which generates the p50 subunit of NF-kappaB. The processing of p105 occurs constitutively in vivo but can be markedly enhanced by various cellular activation agents, although the underlying regulatory mechanism is not yet clear. In the present study, we demonstrate that signal-mediated induction of p105 processing in human T cells is associated with de novo synthesis of this precursor protein. Transient transfection studies performed in COS7 cells revealed that the newly synthesized p105 protein appears to be more rapidly processed compared to its accumulated form that is already associated with the processed product p50. Interestingly, the processing rate of p105 is markedly inhibited in cells co-transfected with p50 or other NF-kappaB subunits, including RelA and c-Rel, that physically interact with p105. These findings suggest that the processing of p105 is subject to negative regulation by the various NF-kappaB subunits. We further demonstrate that p105 undergoes degradation in lipopolysaccharide-stimulated human monocytic cells. However, the inducible degradation of p105 is not coupled with the generation of p50. Together, these studies demonstrate that the processing and inducible degradation of p105 are differentially regulated.
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PMID:Inhibition of p105 processing by NF-kappaB proteins in transiently transfected cells. 864 79

The viral Tax protein, which is encoded by human T-cell leukaemia virus HTLV-I, activates nuclear translocation of the NF-kappa B/Rel transcription factors and relieves cytoplasmic sequestration of RelA and Rel by heterodimerization with NF-kappa B1/p1O5 (refs 1,2). Proteolytic maturation of this precursor protein is performed by the proteasome complex. Here we show that Tax binds specifically to two subunits of the 20S proteasome, HsN3 and HC9. This interaction is weakened with HsN3 and lost for HC9 when a mutant of Tax is substituted that is selectively defective for NF-kappa B activation. Immunoprecipitation shows that p1O5 binds weakly to HC9 and that this interaction is reinforced by Tax. No bridging function of Tax between p1O5 and HsN3 was observed. From these results, we propose that Tax accelerates the proteolytic maturation of P105 by favouring its anchorage to the proteasome.
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PMID:Effects on NF-kappa B1/p105 processing of the interaction between the HTLV-1 transactivator Tax and the proteasome. 869 72

The proteasome-like ClpP protease is widely distributed and structurally conserved among bacteria and eukaryotic cell organelles. In Chlamydomonas eugametos, however, the chloroplast clpP gene predicted a much larger ClpP protein containing large insertion sequences (ISs). One insertion sequence, IS2, is 456 amino acid residues long and not similar to known proteins. Here we show that IS2 is an unusual intein, and its protein splicing activity in Escherichia coli cells can be activated by a single amino acid substitution. Analysis of IS2 sequence revealed short sequence motifs that are similar to known intein motifs, including putative LAGLI-DADG endonuclease motifs. But a histidine residue conserved at the C terminus of known inteins is replaced in the IS2 sequence by a glycine residue (Gly455), rendering the IS2 sequence incapable of detectable protein splicing when tested in E. coli cells. Changing Gly455 to histidine activated the ability of IS2 to undergo protein splicing in E. coli cells. The IS2 sequence (intein) was precisely excised from a precursor protein, with the flanking sequences (exteins) joined together by a normal peptide bond.
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PMID:Identification of an unusual intein in chloroplast ClpP protease of Chlamydomonas eugametos. 911 46

We isolated and sequenced a cDNA encoding mouse proteasome subunit LMP3 from a macrophage cDNA library. The gene encodes a 264-amino-acid protein with a calculated molecular mass of 29.11 kDa and an isoelectric point (pI) of 5.44. Comparison of the predicted protein sequence with that of the human and rat homologues, N3, revealed 11 and eight changes, respectively, in the cleaved NH2-terminal presequence of the precursor protein (pre-LMP3), and six and 10 changes, respectively, in the processed product. To corroborate the predicted molecular mass and pI, we analyzed LMP3 by immunoprecipitation with a mAb to human N3 that crossreacts with mouse LMP3. Precursor and processed forms of LMP3 were identified by 2D NEPHGE-PAGE, and their mobilities suggest the Lmp3 clone encodes the entire protein sequence.
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PMID:Cloning and characterization of mouse Lmp3 cDNA, encoding a proteasome beta subunit. 919 41

Subunit rLMP7 of the multicatalytic proteinase (MCP), which has been associated with chymotrypsin-like proteinase activity, was examined in rat liver and hepatocyte-derived cell lines. rLMP7 was detected in both nucleus and cytosol in liver by immunohistochemistry and immunoblotting, using a peptide-specific anti-rLMP7 antibody. A M(r) 30,000 precursor protein was present only in cytosol, as was a minor component of M(r) 25,000. Mature rLMP7 (M(r) 23,000) was present in MCP in both nucleus and cytosol, although it was not detectable in the nuclear scaffold. Two rLMP7 cDNAs (designated rLMP7.1 and rLMP7.s) were identified by rapid amplification of 5' ends using RT/PCR, a result which was confirmed by Northern blot analysis and RNase protection assays. rLMP7.1 is 3-4x more abundant than rLMP7.s; it is 50 nt longer than the previously reported cDNA sequence and includes an upstream in-frame ATG within a consensus translation initiation sequence, which encodes the M(r) 30,000 rLMP7 precursor protein identified in vivo. rLMP7.s is 100 nt shorter than rLMP7.1 and does not contain the most 5' ATG. Transient transfection analyses with rLMP7.1 and rLMP7.s constructs coupled to green fluorescent protein showed that both transcripts were efficiently expressed in vivo. In vitro expression of these two rLMP7 cDNAs showed that rLMP7.1 produces the M(r) 30,000 precursor protein, whereas rLMP7.s produces two smaller peptides of M(r) 25,000 and 23,000. Purified 20S MCP preparations were able to proteolytically process the M(r) 30,000 precursor to the M(r) 25,000 product but not to the mature rLMP7 form. However, incorporation of this processed M(r) 25,000 product (or of either M(r) form produced from rLMP7.s) did not occur in vitro. In vitro processing and pulse-chase experiments suggested that the mature M(r) 23,000 subunit is derived, at least in part, from the M(r) 30,000 precursor. The M(r) 25,000 form may be a stable product produced directly from rLMP7.s.
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PMID:Studies on rLMP7, a beta-subunit of the multicatalytic proteinase. 922 75

Amyloid precursor protein (APP) is a secretory membrane-bound protein that undergoes restrictive proteolysis and degradation with a short life span in the constitutive secretory pathway or in the endosomal/lysosomal compartment. The degradation machinery, including cellular trafficking and the restrictive cleavage of APP, is poorly understood. To gain further insight into the intracellular degradation mechanism of APP, we searched for effector proteins that interact with APP. We found that a cytosolic molecular chaperon, Hsc73, effectively interacts with the cytoplasmic domain of APP in the presence of proteasome inhibitors. Hsc73 binds to the cytoplasmic domain near the post-transmembrane region of APP and not to the KFERQ-related sequence, KFFEQ, at the C-terminal tail that is assumed to be the selective targeting signal for lysosomal proteolysis. The amounts of Hsc73 that bind to several APP species such as those found in pathological Familial Alzheimer's disease (FAD), Swedish, or Dutch type mutation, are almost identical, suggesting that an abnormal conformation around the secretory cleavage site or a pathological imbalance in APP processing are not irrelevant to the efficiency of Hsc73 binding.
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PMID:Proteasome inhibitors induce the association of Alzheimer's amyloid precursor protein with Hsc73. 992 Aug 21

The transcription factor NF-kappaB is composed of homodimeric and heterodimeric complexes of Rel/NF-kappaB-family polypeptides, which include Rel-A, c-Rel, Rel-B, NF-kappaB/p50 and NF-kappaB2/p52 . The NF-kappaB1 gene encodes a larger precursor protein, p105, from which p50 is produced constitutively by proteasome-mediated removal of the p105 carboxy terminus. The p105 precursor also acts as an NFkappaB-inhibitory protein, retaining associated p50, c-Rel and Rel-A proteins in the cytoplasm through its carboxy terminus. Following cell stimulation by agonists, p105 is proteolysed more rapidly and released Rel subunits translocate into the nucleus. Here we show that TPL-2 , which is homologous to MAP-kinase-kinase kinases in its catalytic domain, forms a complex with the carboxy terminus of p105. TPL-2 was originally identified, in a carboxy-terminal-deleted form, as an oncoprotein in rats and is more than 90% identical to the human oncoprotein COT. Expression of TPL-2 results in phosphorylation and increased degradation of p105 while maintaining p50 production. This releases associated Rel subunits or p50-Rel heterodimers to generate active nuclear NF-kappaB. Furthermore, kinase-inactive TPL-2 blocks the degradation of p105 induced by tumour-necrosis factor-alpha. TPL-2 is therefore a component of a new signalling pathway that controls proteolysis of NF-kappaB1 p105.
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PMID:TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105. 995 Apr 30

A highly fluorescent mutant form of the green fluorescent protein (GFP) has been fused to the human nuclear factor kappaB (NF-kappaB) p50 and p105 (p50/IkappaB gamma), a precursor protein of NF-kappaB p50. GFP-p50 and GFP-p105 were expressed in monkey COS-7 cells and human HeLa cells. Translocation of these chimeric proteins was observed by confocal laser scanning microscopy. GFP-p50 (without IkappaB gamma) in the transfected cells resided in the nucleus. On the other hand, GFP-p105 (GFP-p50 with IkappaB gamma) localized only in the cytoplasm before stimulation and translocated to the nucleus with stimulant specificity similar to that of native NF-kappaB/IkappaB. In addition, the translocation of NF-kappaB to the nucleus had a distinct lag time (a quiescent time) in the target cells. The lag time lasted 10-20 min after stimulation with hydrogen peroxide or tumor necrosis factor alpha. It was suggested that this might be due to the existence of a limiting step where NF-kappaB is released from NF-kappaB/IkappaB by the proteasome.
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PMID:Nuclear translocation of green fluorescent protein-nuclear factor kappaB with a distinct lag time in living cells. 1003 37

The ubiquitin proteolytic system plays a major role in a variety of basic cellular processes. In the majority of these processes, the target proteins are completely degraded. In one exceptional case, generation of the p50 subunit of the transcriptional regulator NF-kappaB, the precursor protein p105 is processed in a limited manner: the N-terminal domain yields the p50 subunit, whereas the C-terminal domain is degraded. The identity of the mechanisms involved in this unique process have remained elusive. It has been shown that a Gly-rich region (GRR) at the C-terminal domain of p50 is an important processing signal. Here we show that the GRR does not interfere with conjugation of ubiquitin to p105 but probably does interfere with the processing of the ubiquitin-tagged precursor by the 26S proteasome. Structural analysis reveals that a short sequence containing a few Gly residues and a single essential Ala is sufficient to generate p50. Mechanistically, the presence of the GRR appears to stop further degradation of p50 and to stabilize the molecule. It appears that the localization of the GRR within p105 plays an important role in directing processing: transfer of the GRR within p105 or insertion of the GRR into homologous or heterologous proteins is not sufficient to promote processing in most cases, which is probably due to the requirement for an additional specific ubiquitination and/or recognition domain(s). Indeed, we have shown that amino acid residues 441 to 454 are important for processing. In particular, both Lys 441 and Lys 442 appear to serve as major ubiquitination targets, while residues 446 to 454 are independently important for processing and may serve as the ubiquitin ligase recognition motif.
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PMID:Structural motifs involved in ubiquitin-mediated processing of the NF-kappaB precursor p105: roles of the glycine-rich region and a downstream ubiquitination domain. 1020 90

The optimal level of oxygen-dependent microbicidal activity in human neutrophils depends on the generation of highly toxic products, including hypochlorous acid, by hydrogen peroxide in the presence of chloride anion and the neutrophil granule protein myeloperoxidase (MPO). The biosynthesis of MPO is normally restricted to the promyelocytic stage of myeloid development and includes N-linked glycosylation, heme insertion, proteolytic processing, subunit dimerization, and eventual targeting to the azurophilic granule. In the endoplasmic reticulum, MPO precursors interact transiently with calreticulin and calnexin, presumably in their capacity as molecular chaperones. In light of the important role of the MPO-H2O2-chloride system in human host defense, the relatively high prevalence of inherited MPO deficiency was an unanticipated insight provided by the widespread use of automated flow cytometry for the enumeration of leukocytes in clinical specimens. In many cases of inherited MPO deficiency, affected neutrophils have immunochemical evidence of precursor protein but lack the subunits of mature MPO, peroxidase activity, or the ability to chlorinate target proteins. To date, four genotypes have been reported to cause inherited MPO deficiency, each of which results in missense mutations. In the genotype Y173C, the mutant precursor is retained in the endoplasmic reticulum by virtue of its prolonged interaction with calnexin, and it eventually undergoes degradation in the 20S proteasome. In this way, the quality control system operating in the endoplasmic reticulum retrieves malfolded MPO precursors from the biosynthetic pathway and creates the biochemical phenotype of MPO deficiency. Thus MPO deficiency caused by Y173C joins the ranks of cystic fibrosis, protein C deficiency, and other genetic disorders that reflect abnormalities in protein folding.
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PMID:Quality control in the endoplasmic reticulum: lessons from hereditary myeloperoxidase deficiency. 1048 5


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