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 reverse transcription polymerase chain reaction (RT-PCR) with primers specific for each of the 14 exons of the human complement regulatory protein membrane cofactor protein (MCP;CD46) has been utilized to determine MCP mRNA transcript expression in peripheral blood mononuclear cells (PBMC). An additional transcript of a larger size than predicted was consistently detected in reactions with a sense primer for exon 7, that encodes the first alternatively spliced serine-threonine-rich region (ST-A), together with an antisense exon 12 primer, RT-PCR with primers for other exons both 5' and 3' of exon 7 further showed that these MCP transcripts contain additional sequences immediately both 5' and 3' to the exon 7-encoded sequence. Comparison of genomic DNA with cDNA by PCR, in combination with sequence analysis, demonstrated the presence of the complete invariant sequences of both introns adjacent to exon 7, i.e. intron 6 (411 bp) and intron 7 (127 bp). RT-PCR using primers specific for the intron 6 sequence, together with Southern and Northern blotting using an intron 6-specific probe, confirmed retention of this intron within a novel 4.8-kb mRNA transcript in human PBMC. Due to the presence of a stop codon within intron 6, translation would result in a novel truncated MCP isoform (MCPi) containing the four invariant short consensus repeat (SCR) regions and a unique C-terminal 39 amino acid transmembrane and cytoplasmic tail region that may promote endoplasmic reticulum retention.
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PMID:A novel isoform of human membrane cofactor protein (CD46) mRNA generated by intron retention. 966 62

Membrane cofactor protein (MCP; CD46) is a type 1 membrane glycoprotein that inhibits complement activation on host cells. It also is a measles virus (MV) receptor, an adherence factor for group A Streptococcus pyogenes, and a cellular pilus receptor for pathogenic Neisseria. The amino terminus of MCP consists of four complement control protein (CCP) repeats, three of which (CCP-1, -2, and -4) possess N-glycans. Immediately following the CCP modules is an alternatively spliced region for extensive O-glycosylation (termed the STP domain). Previous studies established that the N-glycan of CCP-2 is essential for MV binding and infection and that the splicing variants of the STP domain not only affect MV binding and fusion, but also differentially protect against complement-mediated cytolysis. In this report, we dissect the role of these carbohydrates on complement regulatory function. We constructed, expressed, and characterized proteins deleting these carbohydrates. For MCP-mediated protection against cytolysis, the N-glycans of CCP-2 and -4 were necessary, the STP segment influenced but was not essential, and the N-glycan of CCP-1 was not required. In addition, the rate and magnitude of cell surface cleavage of C4b to C4c and C4d by MCP and factor I correlated with cytoprotection. These studies expand the structure-function understanding of the active sites of MCP and elucidate an important role for carbohydrates in its function, a finding consistent with their conservation in the MCP of other species.
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PMID:Membrane cofactor protein: importance of N- and O-glycosylation for complement regulatory function. 975 96

The human asialoglycoprotein receptor H2a precursor, a type II membrane protein, is cleaved to a soluble form that is secreted. Uncleaved precursor molecules are completely retained in the endoplasmic reticulum (ER) and degraded by the proteasome. To find out the causes of its fate we studied folding of H2a precursor, which was very similar to that of its alternatively spliced variant H2b which can exit to the Golgi. Proteasomal inhibition led to accumulation of folded rather than unfolded molecules. Accumulation of ER-retained H2a did not cause an unfolded protein response. Although the receptor is a heterooligomer of the H1 and H2 subunits, single expression led to some self-assembly. Whereas these homooligomers accumulated for H2b they were degraded for H2a. Translocation of H2a into the ER occurred efficiently. Therefore, the retention and proteasomal degradation of uncleaved membrane-bound H2a precursor from the ER do not involve aberrant translocation or misfolding and are not prevented by self-assembly.
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PMID:Folding and self-assembly do not prevent ER retention and proteasomal degradation of asialoglycoprotein receptor H2a. 1057 Oct 71

The human gene CC3 is a metastasis suppressor for small cell lung carcinoma (SCLC) in vivo. The ability of CC3 to impair the apoptotic resistance of tumor cells is likely to contribute to metastasis suppression. We describe here an alternatively spliced RNA of CC3, designated TC3, that encodes an unstable protein with antiapoptotic activity. TC3 and CC3 proteins share amino-terminal sequences, but TC3 has a unique short hydrophobic carboxyl terminus. Overexpression of CC3 results in massive death of rodent fibroblasts, but TC3 protects cells from CC3-induced death and from other death stimuli such as treatment with tumor necrosis factor or overexpression of Bax protein. The death-inducing activity of CC3 resides within its amino-terminal domain, which is conserved in TC3. The carboxyl terminus of TC3 is responsible for the antiapoptotic function of TC3; mutations in this domain abolish the ability of TC3 to protect cells from apoptosis. TC3 protein is short-lived due to its rapid degradation by proteasome, and it forms complexes with a regulatory subunit of proteasome known as s5alpha. The signal for the rapid degradation of TC3 resides within its carboxyl terminus, which is capable of conferring instability on a heterologous protein. The proapoptotic activity of CC3 in SCLC cells is induced by a wide variety of signals and involves disruption of the mitochondrial membrane potential (Deltapsim). The CC3 protein has sequence similarity to bacterial short-chain dehydrogenases/reductases and might represent a phylogenetically old effector of cell death similar to the recently identified apoptosis-inducing factor. CC3 and TC3 have opposing functions in apoptosis and represent a novel dual regulator of cell death.
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PMID:Alternatively spliced products CC3 and TC3 have opposing effects on apoptosis. 1061 Dec 37

The monocyte chemotactic protein-1 (MCP-1) receptor (MCP-1R) is expressed on monocytes, a subpopulation of memory T lymphocytes, and basophils. Two alternatively spliced forms of MCP-1R, CCR2A and CCR2B, exist and differ only in their carboxyl-terminal tails. To determine whether CCR2A and CCR2B receptors function similarly, Jurkat T cells were stably transfected with plasmids encoding the human CCR2A or CCR2B gene. Nanomolar concentrations of MCP-1 induced chemotaxis in the CCR2B transfectants that express high, intermediate, and low levels of MCP-1R. Peak chemotactic activity was shifted to the right as receptor number decreased. Five-fold more MCP-1 was required to initiate chemotaxis of the CCR2A low transfectant, but the peak of chemotaxis was similar for the CCR2A and CCR2B transfectants expressing similar numbers of receptors. MCP-1-induced chemotaxis was sensitive to pertussis toxin, implying that both CCR2A and CCR2B are G(i)alpha protein coupled. MCP-1 induced a transient Ca(2+) flux in the CCR2B transfectant that was partially sensitive to pertussis toxin. In contrast, MCP-1 did not induce Ca(2+) flux in the CCR2A transfectant. Since MCP-1 can stimulate chemotaxis of the CCR2A transfectant without inducing Ca(2+) mobilization, Ca(2+) flux may not be required for MCP-1-induced chemotaxis in the Jurkat transfectants. These results indicate that functional differences exist between the CCR2A and CCR2B transfectants that can be attributed solely to differences in the carboxyl-terminal tail.
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PMID:Functional differences between monocyte chemotactic protein-1 receptor A and monocyte chemotactic protein-1 receptor B expressed in a Jurkat T cell. 1104 12

Our previous studies indicated that an alternatively spliced variant mRNA of p40-phox, a cytosolic component of NADPH oxidase, is expressed but its protein is hardly detected in myeloid cells such as promyelocytic HL-60 cells and neutrophils. Here, we have examined the stability of p40-phox variant protein in undifferentiated HL-60 cells. When in vitro-translated proteins were incubated with subcellular fractions of HL-60 cells, p40-phox variant protein but not native p40-phox was degraded by the cytosol and granule fractions. The degradation of variant protein by the granule fraction was observed using sonicated but not intact granules, suggesting that the variant protein is unlikely to be degraded by the granules in intact cells. To identify the enzyme(s) involved, we examined the effects of various enzyme inhibitors on the degradation of variant protein by the cytosol fraction. Degradation was completely inhibited by proline-specific serine protease (prolyl endopeptidase) inhibitors but not by proteasome, calpain, and metalloprotease inhibitors. Furthermore, the variant protein was degraded by a purified prolyl endopeptidase, and the degradation was protected by treating HL-60 cells with a cell-permeable inhibitor (S17092-1) for prolyl endopeptidase. These observations suggest that a cytosolic prolyl endopeptidase is involved in the degradation of p40-phox variant protein in myeloid cells.
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PMID:Involvement of cytosolic prolyl endopeptidase in degradation of p40-phox splice variant protein in myeloid cells. 1140 83

Hypoxia-inducible factor-1alpha (HIF-1alpha), a member of the transcription family characterized by a basic helix-loop-helix (bHLH) domain and a PAS domain, regulates the transcription of hypoxia-inducible genes involved in erythropoiesis, vascular remodelling and glucose/energy metabolism. It contains bHLH/PAS domains in the N-terminal half, and a nuclear localization signal (NLS) and two transactivation domains (TADs) in the C-terminal half. It also has an oxygen-dependent degradation (ODD) domain, which is required to degrade HIF-1alpha protein by the ubiquitin-proteasome pathway. In this study, we identified a new alternatively spliced variant of human HIF-1alpha mRNA, which lacked both exons 11 and 12, producing a frame shift and giving a shorter form of HIF-1alpha. In the corresponding protein, a part of the ODD domain, both TADs and the C-terminal NLS motif were missing. Expression of endogenous HIF-1alpha variant protein was identified using immunoprecipitation and immunoblotting methods. The expressed HIF-1alpha variant exhibited neither the activity of transactivation nor hypoxia-induced nuclear translocation. In contrast with HIF-1alpha, the variant was strikingly stable in normoxic conditions and not up-regulated to such an extent by hypoxia, cobalt ions or desferrioxamine. It was also demonstrated that the HIF-1alpha variant competed with endogenous HIF-1alpha and suppressed HIF-1 activity, resulting in the down-regulation of mRNA expression of hypoxia-inducible genes. The association of the variant and arylhydrocarbon receptor nuclear translocator in the cytoplasm may be related to the inhibition of HIF-1 activity. It is assumed that this isoform preserves the balance between aerobic and anaerobic metabolism by counteracting the overaction of HIF-1alpha.
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PMID:A dominant-negative isoform lacking exons 11 and 12 of the human hypoxia-inducible factor-1alpha gene. 1182 41

In the rat, the -synuclein gene is alternatively spliced and exists in three forms, rat synuclein 1 (rSYN1), synuclein 2 (rSYN2) and synuclein 3. rSYN2 cDNA encodes a 149 amino acid protein that is homologous to rSYN1 and human -synuclein for the first 100 amino acids, but is divergent for the 49 amino acid carboxy-terminal region. We demonstrate here that rSYN2 forms small aggregates throughout the cytoplasm when overexpressed in human H4 cells, whereas rSYN1 expression is diffuse. Inhibition of the proteasome promotes the formation of larger, cytoplasmic rSYN2 inclusions in transfected cells. Although a survey of the available databases suggests that there is no human splice form equivalent of rSYN2, thus arguing against a direct role in Lewy body formation and Parkinson's disease, these data nonetheless suggest that modifications of the carboxy-terminal region of -synuclein predispose it to inclusion formation.
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PMID:An alternatively spliced form of rodent alpha-synuclein forms intracellular inclusions in vitro: role of the carboxy-terminus in alpha-synuclein aggregation. 1195 24

The type-I isoform of pyrimidine 5'-nucleotidase (P5N-I) has an important role in the catabolism of pyrimidine mononucleotides during erythroid maturation. Two alternatively spliced forms of P5N-I mRNA have been identified, and we found another alternatively spliced form in reticulocytes, which included an additional 87-bp sequence. The sequence is located 6.2-kb downstream of the exon 2 and 2.7-kb upstream of the exon 3 sequence; consequently, the P5N-I gene encodes 11 exons, which span approximately 48 kb. We identified five novel mutations in nine families with P5N-I deficiency: two missense mutations (425C, 721C), one splice mutation (339C), one 1-bp insertion (251-insA-252) and one 9-bp deletion (del 192-200). All patients were homozygous for each mutation. The mutant P5N-I with 721C (G241R) had lower affinity for cytidine monophosphate, suggesting that Gly241 is important for substrate binding. Haplotype analysis showed that 721C, which had been identified in five unrelated families, was a founder mutation. The mutant P5N was then expressed in Cos-7. The degradation of P5N with 425C (L142P) was significantly faster than a wild-type control, and proteasome inhibitors restored the stability of L142P. These data suggest that L142P increases susceptibility to the degradation by the ubiquitin-proteasome pathway.
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PMID:Molecular basis of Japanese variants of pyrimidine 5'-nucleotidase deficiency. 1523 49

Embryonic sensory neurons express membrane-anchored growth factors that stimulate proliferation and differentiation of Schwann cells. The most important of these are members of the neuregulin-1 (Nrg-1) family that activate the erbB2/erbB3 receptor kinase on Schwann cells. Nrg-1 growth factors display a complex pattern of alternative mRNA splicing. We investigated the expression of the Nrg-1 type I in rat embryo dorsal root ganglion (DRG) neurons. Nrg-1 type I mRNA was abundantly expressed in DRG neurons; molecular cloning identified three distinct isoforms. The most prominent structural difference produced by alternative splicing was truncation of the C-terminal cytoplasmic domain. In sensory neurons and other cells, Nrg-1 type I proteins with the full-length 374-amino-acid cytoplasmic domain were expressed on the cell surface. In contrast, an isoform with a partially truncated cytoplasmic domain was retained in an intracellular compartment. Deletion studies demonstrated the presence of a cryptic intracellular retention signal that was exposed in the truncated cytoplasmic domain. Cell surface Nrg-1 type I molecules were subject to protease-dependent release of the biologically active ectodomain. As a consequence of their intracellular localization, the Nrg-1 type I isoform with a truncated cytoplasmic domain was not subject to membrane shedding. Nrg-1 type I ectodomain release was accelerated by factors present in Schwann cell-conditioned medium. In cells with active Nrg-1 type I ectodomain, shedding products corresponding to the cytoplasmic domain were not detected, because of rapid gamma-secretase- and proteasome-dependent degradation. These results demonstrate that sensory neurons express alternatively spliced neuregulin polypeptides with distinct subcellular localizations and processing.
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PMID:Neuregulin isoforms in dorsal root ganglion neurons: effects of the cytoplasmic domain on localization and membrane shedding of Nrg-1 type I. 1661 45


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