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

---

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

The nucleotide sequence of a cDNA that encodes a new regulatory subunit, named p40, of the 26S proteasome of human hepatoblastoma HepG2 cells has been determined. The polypeptide predicted from the open reading frame consists of 324 amino acid residues with a calculated molecular mass of 37020 and isoelectric point of 6.03. A KEKE motif, consisting of a very hydrophilic domain rich in 'alternating' lysine (positive) and glutamate (negative) residues, is present in the C-terminus of p40. The overall structure of p40 is homologous to that of the mouse Mov-34 gene product, whose gene disruption by proviral integration results in a recessive embryonic lethality. Thus the p40/Mov-34 protein is a novel essential regulatory subunit of the human 26S proteasome.
...
PMID:cDNA cloning of p40, a regulatory subunit of the human 26S proteasome, and a homolog of the Mov-34 gene product. 775 39

A stretch of 28 'alternating' lysine (K) and glutamate (E) residues is found in an activator of the multicatalytic protease. Such 'KEKE sequences' are also present in subunits of the multicatalytic protease, in subunits of the 26S protease and in a variety of chaperonins. We propose that KEKE regions promote association between protein complexes. Furthermore, they may contribute to the selection of peptides presented on MHC Class I receptors.
...
PMID:KEKE motifs. Proposed roles in protein-protein association and presentation of peptides by MHC class I receptors. 803 24

Tetanus and botulinum neurotoxins constitute a new group of Zn-endopeptidases which has been recently actively investigated with the purpose of correlating their biochemical properties to their neurobiocytosis inhibitory capacity. Crystallographic data show that Zn-endopeptidases are characterized by an active site with a Zn atom coordinated to two histidines and glutamate-bound water molecule. The two histidines and glutamate resides belong to the HEXXH motif which is characteristic of most Zn-endopeptidases. A forth metal ligand is a glutamate in thermolysin-like proteinases, but it is an histidine in the astacin family of proteinases and in alkaline protease. Astacin and alkaline protease possess a tyrosine as fifth Zn ligand, whose position in the case of alkaline protease could not be determined by X-ray crystallography. Not much is known about the atom arrangement around the active site in tetanus neurotoxin. In this work X-ray absorption spectroscopy has been used to obtain information on the Zn coordination mode in tetanus neurotoxin. The near-edge and extended fine-structure absorption spectra of this toxin are compared with those of astacin, alkaline protease and thermolysin. The present data and sequence information suggest a new pattern of Zn coordination in tetanus neurotoxin with one water molecule and three aromatic residues as metal ligands. These residues are the two histidines of the characteristic motif and a tyrosine which is tentatively identified with Tyr242, on the basis of sequence comparison and mutagenesis experiments. The mean distances of the Zn from the nearest coordinated atoms is reported. Our results indicate that alkaline protease, like astacin, also possesses a tyrosine as a fifth ligand.
...
PMID:X-ray absorption spectroscopy study of zinc coordination in tetanus neurotoxin, astacin, alkaline protease and thermolysin. 865 8

The retinoids are reported to reduce incidence of second primary aerodigestive cancers. Mechanisms for this chemoprevention are previously linked to all-trans retinoic acid (RA) signaling growth inhibition at G1 in carcinogen-exposed immortalized human bronchial epithelial cells. This study investigated how RA suppresses human bronchial epithelial cell growth at the G1-S cell cycle transition. RA signaled growth suppression of human bronchial epithelial cells and a decline in cyclin D1 protein but not mRNA expression. Exogenous cyclin D1 protein also declined after RA treatment of transfected, immortalized human bronchial epithelial cells, suggesting that posttranslational mechanisms were active in this regulation of cyclin D1 expression. Findings were extended by showing treatment with ubiquitin-dependent proteasome inhibitors: calpain inhibitor I and lactacystin each prevented this decreased cyclin D1 protein expression, despite RA treatment. Treatment with the cysteine proteinase inhibitor, E-64, did not prevent this cyclin D1 decline. High molecular weight cyclin D1 protein species appeared after proteasome inhibitor treatments, suggesting that ubiquitinated species were present. To learn whether RA directly promoted degradation of cyclin D1 protein, studies using human bronchial epithelial cell protein extracts and in vitro-translated cyclin D1 were performed. In vitro-translated cyclin D1 degraded more rapidly when incubated with extracts from RA treated vs. untreated cells. Notably, this RA-signaled cyclin D1 proteolysis depended on the C-terminal PEST sequence, a region rich in proline (P), glutamate (E), serine (S), and threonine (T). Taken together, these data highlight RA-induced cyclin D1 proteolysis as a mechanism signaling growth inhibition at G1 active in the prevention of human bronchial epithelial cell transformation.
...
PMID:Posttranslational regulation of cyclin D1 by retinoic acid: a chemoprevention mechanism. 934 64

The NMDA-type glutamate receptor agonist quinolinic acid (QA), which causes tissue lesions in the rat brain as well as cell loss in neuronal cultures, is widely used in models of glutamate excitotoxicity. The aim of this study was to evaluate the alterations in gene expression in a primary hippocampal cell culture after exposure to QA. By means of differential mRNA display, we were able to pinpoint as many as 23 bands which appeared to be upregulated after a 6-h treatment with quinolinic acid. The differential expression of 13 cDNAs could be confirmed by dot blot and/or Northern analysis. Of the cDNAs, the p112 regulatory subunit of the 26S proteasome, a PDGF-associated protein and the glia-derived protease nexin PN-1 could be identified. The results provide emphasis to the participation of proteolysis and protease inhibition in neurodegenerative processes.
...
PMID:Differentially expressed genes in hippocampal cell cultures in response to an excitotoxic insult by quinolinic acid. 975 68

The metabolic fluxes through the central carbon pathways in the bioprocess for serine alkaline protease (SAP) production by Bacillus licheniformis were calculated by the metabolic flux-based stoichiometric model based on the proposed metabolic network that contains 102 metabolites and 133 reaction fluxes using the time profiles of citrate, dry cell, organic acids, amino acids, and SAP as the constraints. The model was solved by minimizing the SAP accumulation rate in the cell. The effects of the oxygen-transfer rate (OTR) on the metabolic fluxes were investigated in a defined medium where citrate was used as the sole carbon source. The central pathways were active for the growth and the SAP synthesis in all the periods of the bioprocess at low (LOT), medium (MOT), and high (HOT) oxygen-transfer conditions. The flux partitioning in the TCA cycle at alpha-ketoglutarate towards glutamate group and at oxalacetate (OA) toward aspartic acid group amino acids were dependent on the OTR. The flux of the anaplerotic reaction that connects the TCA cycle either from malate or OA to the gluconeogenesis pathway via the main branch point pyruvate (Pyr) was also influenced by the OTR. With the decrease in the OTR, the intracellular flux values after glycerate 3-phosphate (PG3) in the gluconeogenesis pathway and the specific growth rate decreased. The total ATP-generation rate increased with the increase in OTR. The pathway towards the aspartic acid family amino acids which is important for sporulation that precedes the SAP synthesis were all active throughout the bioprocess. Metabolic flux analysis results at LOT, MOT, and HOT conditions encourage the design of an oxygen-transfer strategy in the bioreactor; moreover, asparagine synthetase or aspartate kinase could be the potential metabolic engineering sites due to the low value of the flux from the branch point aspartate toward asparagine.
...
PMID:Metabolic flux analysis for serine alkaline protease fermentation by Bacillus licheniformis in a defined medium: effects of the oxygen transfer rate. 1039 51

Polypeptide sequences enriched in proline (P), glutamate (E), serine (S), and threonine (T), dubbed PEST domains, are proposed to expedite the degradation of proteins. The proteolysis of one PEST-containing protein, IkappaBalpha, is prerequisite to the activation of the transcription factor NF-kappaB. Two mechanisms of IkappaBalpha degradation in vivo have been described, one well characterized through the ubiquitin-proteasome pathway, and another less characterized through calpain. In this report, a mutational analysis was done to identify any regions of IkappaBalpha that facilitate its recognition and proteolysis by calpain in vitro. These studies revealed that the PEST sequence of IkappaBalpha is critical for its calpain-dependent degradation. Furthermore, the IkappaBalpha-PEST domain binds to the calmodulin-like domain of the large subunit of mu-calpain (muCaMLD). Transfer of the IkappaBalpha-PEST domain to a protein incapable of either binding to or being degraded by mu-calpain allowed for the interaction of the chimeric protein with muCaMLD and resulted in its susceptibility to calpain proteolysis. Moreover, the muCaMLD of calpain acts as a competitive inhibitor of calpain-dependent IkappaBalpha degradation. Our data demonstrate that the IkappaBalpha-PEST sequence acts as a modular domain to promote the physical association with and subsequent degradation by mu-calpain and suggest a functional role for PEST sequences in other proteins as potential calpain-targeting units.
...
PMID:The PEST domain of IkappaBalpha is necessary and sufficient for in vitro degradation by mu-calpain. 1052 80

Maltose permease is required for maltose transport into Saccharomyces cells. Glucose addition to maltose-fermenting cells causes selective delivery of this integral plasma membrane protein to the yeast vacuole via endocytosis for degradation by resident proteases. This glucose-induced degradation is independent of the proteasome but requires ubiquitin and certain ubiquitin conjugating enzymes. We used mutation analysis to identify target sequences in Mal61/HA maltose permease involved in its selective glucose-induced degradation. A nonsense mutation was introduced at codon 581, creating a truncated functional maltose permease. Additional missense mutations were introduced into the mal61/HA-581NS allele, altering potential phosphorylation and ubiquitination sites. No significant effect was seen on the rate of glucose-induced degradation of these mutant proteins. Deletion mutations were constructed, removing residues 2-30, 31-60, 61-90, and 49-78 of the N-terminal cytoplasmic domain, as well as a missense mutation of a dileucine motif. Results indicate that the proline-, glutamate-, aspartate-, serine-, and threonine-rich (PEST) sequence found in the N-terminal cytoplasmic domain, particularly residues 49-78, is required for glucose-induced degradation of Mal61/HAp and for the rapid glucose-induced inactivation of maltose transport activity. The decreased rate of glucose-induced degradation correlates with a decrease in the level of glucose-induced ubiquitination of the DeltaPEST mutant permease. In addition, newly synthesized mutant permease proteins lacking residues 49-78 or carrying an alteration in the dileucine motif, residues 69 and 70, are resistant to glucose-induced inactivation of maltose transport activity. This N-terminal PEST-like sequence is the target of both the Rgt2p-dependent and the Glc7p-Reg1p-dependent glucose signaling pathways.
...
PMID:A PEST-like sequence in the N-terminal cytoplasmic domain of Saccharomyces maltose permease is required for glucose-induced proteolysis and rapid inactivation of transport activity. 1075 1

Repeated exposure of human skin to solar UV radiation leads to premature aging (photoaging) and skin cancer. UV-induced skin damage can be ameliorated by all-trans retinoic acid treatment. The actions of retinoic acid in skin keratinocytes are mediated primarily by nuclear retinoic acid receptor gamma (RARgamma) and retinoid X receptor alpha (RXRalpha). We found that exposure of cultured primary human keratinocytes to UV irradiation (30 mJ/cm2) substantially reduced (50-90%) RARgamma and RXRalpha mRNA and protein within 8 h. The rates of disappearance of RARgamma and RXRalpha proteins after UV exposure or treatment with the protein synthesis inhibitor cycloheximide were similar. UV irradiation did not increase the rate of breakdown of RARgamma or RXRalpha but rather reduced their rate of synthesis. The addition of proteasome inhibitors MG132 and LLvL, but not the lysosomal inhibitor E64, prevented loss of RARgamma and RXRalpha proteins after exposure of keratinocytes to either UV radiation or cycloheximide. Soluble extracts from nonirradiated or UV-irradiated keratinocytes possessed similar levels of proteasome activity that degraded RARgamma and RXRalpha proteins in vitro. Furthermore, RARgamma and RXRalpha were polyubiquitinated in intact cells. RXRalpha was found to contain two proline, glutamate/aspartate, serine, and threonine (PEST) motifs, which confer rapid turnover of many short-lived regulatory proteins that are degraded by the ubiquitin/proteasome pathway. However, the PEST motifs in RXRalpha did not function to regulate its stability, because deletion of the PEST motifs individually or together did not alter ubiquitination or proteasome-mediated degradation of RXRalpha. These results demonstrate that loss of RARgamma and RXRalpha proteins after UV irradiation results from degradation via the ubiquitin/proteasome pathway. Taken together, the data here indicate that ubiquitin/proteasome-mediated breakdown is an important mechanism regulating the levels of nuclear retinoid receptors.
...
PMID:Ubiquitin/proteasome pathway regulates levels of retinoic acid receptor gamma and retinoid X receptor alpha in human keratinocytes. 1078 91

The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. N-terminal asparagine and glutamine are tertiary destabilizing residues, in that they are enzymatically deamidated to yield secondary destabilizing residues aspartate and glutamate, which are conjugated to arginine, a primary destabilizing residue. N-terminal arginine of a substrate protein is bound by the Ubr1-encoded E3alpha, the E3 component of the ubiquitin-proteasome-dependent N-end rule pathway. We describe the construction and analysis of mouse strains lacking the asparagine-specific N-terminal amidase (Nt(N)-amidase), encoded by the Ntan1 gene. In wild-type embryos, Ntan1 was strongly expressed in the branchial arches and in the tail and limb buds. The Ntan1(-/-) mouse strains lacked the Nt(N)-amidase activity but retained glutamine-specific Nt(Q)-amidase, indicating that the two enzymes are encoded by different genes. Among the normally short-lived N-end rule substrates, only those bearing N-terminal asparagine became long-lived in Ntan1(-/-) fibroblasts. The Ntan1(-/-) mice were fertile and outwardly normal but differed from their congenic wild-type counterparts in spontaneous activity, spatial memory, and a socially conditioned exploratory phenotype that has not been previously described with other mouse strains.
...
PMID:Altered activity, social behavior, and spatial memory in mice lacking the NTAN1p amidase and the asparagine branch of the N-end rule pathway. 1080 55


1 2 3 4 5 6 7 8 9 10 Next >>

---