Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteasomes play a key role in the degradation of abnormal proteins, of short-lived regulatory proteins and in antigen processing. Evidence is accumulating that the 20 S proteasome represents the proteolytic core of the 26 S protease complex (26 S proteasome) which contains several additional subunits implicated in regulation and substrate recognition. Using electron microscopy and digital image analysis we obtained first insights into the structure of this complex which has an estimated molecular weight of approximately 2000 kDa. Two highly asymmetric masses which presumably contain the regulatory subunits of the 26 S complex are attached to both ends of the dimeric 20 S proteasome clearly reflecting its C2 symmetry. The structural uniformity of the complex, i.e. the absence of significant inter-image variations, has important implications for the structure of the latter: It indicates that, in spite of their sequence similarities, the various alpha-type and beta-type subunits of the 20 S proteasome are not promiscuous but occupy precisely defined positions.
J Mol Biol 1993 Dec 20
PMID:Structural features of the 26 S proteasome complex. 826 38

A locus on human chromosome 16q22.1 contains at least five tightly clustered genes which are unrelated by sequence homology and apparently unrelated by function. The genes for a putative proteasome subunit (MECL 1), a chymotrypsin-like protease (CTRL), a protein serine kinase (PSKH1), the previously cloned lecithin:cholesterol acyl transferase (LCAT) and a protein of unknown function are found within 40 kb of genomic DNA. Exons from the former four genes are located within a 12 kb region including a CpG island associated with the putative proteasome gene. Three of the genes are widely expressed, whereas the genes for the protease and LCAT are highly tissue specific. The distance between the transcriptional units of the gene upstream of LCAT and LCAT is only 199 bp. Alternative polyadenylation of the protease transcripts creates a transcription unit which overlaps with the oppositely oriented kinase gene. The selective advantage of this unusual gene clustering may involve transcriptional interference(s) and coregulatory events not yet understood. Given the current estimate of about 100,000 genes in the human genome, our findings support the notion that genes are not evenly distributed.
Hum Mol Genet 1993 Oct
PMID:A tight cluster of five unrelated human genes on chromosome 16q22.1. 826 11

The 26S protease complex was purified from chick skeletal muscle and shown to consist of unusually heterogeneous 21-140 kDa polypeptides, including the 21-32 kDa subunits of the 20S proteasome. Electron microscopic analysis revealed that the 26S complex may have a symmetric morphology with two large rectangular terminal domains attached to a thinner central 20S proteasome domain. The 26S complex was capable of degrading the peptide substrates of the 20S proteasome, including Suc-LLVY-AMC, N-Cbz-LLE-NA and N-Cbz-ARR-MNA. The two enzyme complexes showed similar sensitivities to various site-specific protease inhibitors, although their sensitivities to SDS were differed from each other. Immunoprecipitation with anti-26S complex antibody reduced peptide hydrolysis by the 20S proteasome. Similarly, anti-20S proteasome antibody inhibited peptide hydrolysis by the 26S complex. These results demonstrate that the 26S protease complex contains the 20S proteasome as a functional and structural component.
Biochem Mol Biol Int 1993 May
PMID:Structure and properties of the 26S protease complex from chick skeletal muscle. 835 24

Proteasomes are abundant, multisubunit protein complexes found in the cytoplasm and nucleus of eukaryotic cells that catalyze both ubiquitin-dependent and ubiquitin-independent protein degradation. In addition to their role in normal protein turnover, proteasomes are believed to be involved in the production of most antigenic peptides presented to T cells by major histocompatibility complex (MHC) class I molecules. A distinct subset of mouse proteasomes contain a subunit called LMP-2, which is encoded within the MHC. Here we demonstrate that a previously isolated proteasome cDNA clone encodes the LMP-2 subunit, and that two distinct forms of this subunit may be found in the proteasome complex. One form probably corresponds to the primary translation product, whereas the second form appears to be post-translationally processed by removal of the amino-terminal 20 amino acids. Determination of the location of intron/exon boundaries in the Lmp-2 gene indicated that these residues correspond precisely to the first exon of the gene.
Mol Immunol 1993 Sep
PMID:Post-translational processing of a major histocompatibility complex-encoded proteasome subunit, LMP-2. 841 22

The transcription factor c-Fos is a short-lived cellular protein. The levels of the protein fluctuate significantly and abruptly during changing pathophysiological conditions. Thus, it is clear that degradation of the protein plays an important role in its tightly regulated activity. We examined the involvement of the ubiquitin pathway in c-Fos breakdown. Using a mutant cell line, ts20, that harbors a thermolabile ubiquitin-activating enzyme, E1, we demonstrate that impaired function of the ubiquitin system stabilizes c-Fos in vivo. In vitro, we reconstituted a cell-free system and demonstrated that the protein is multiply ubiquitinated. The adducts serve as essential intermediates for degradation by the 26S proteasome. We show that both conjugation and degradation are significantly stimulated by c-Jun, with which c-Fos forms the active heterodimeric transcriptional activator AP-1. Analysis of the enzymatic cascade involved in the conjugation process reveals that the ubiquitin-carrier protein E2-F1 and its human homolog UbcH5, which target the tumor suppressor p53 for degradation, are also involved in c-Fos recognition. The E2 enzyme acts along with a novel species of ubiquitin-protein ligase, E3. This enzyme is distinct from other known E3s, including E3 alpha/UBR1, E3 beta, and E6-AP. We have purified the novel enzyme approximately 350-fold and demonstrated that it is a homodimer with an apparent molecular mass of approximately 280 kDa. It contains a sulfhydryl group that is essential for its activity, presumably for anchoring activated ubiquitin as an intermediate thioester prior to its transfer to the substrate. Taken together, our in vivo and in vitro studies strongly suggest that c-Fos is degraded in the cell by the ubiquitin-proteasome proteolytic pathway in a process that requires a novel recognition enzyme.
Mol Cell Biol 1995 Dec
PMID:Degradation of the proto-oncogene product c-Fos by the ubiquitin proteolytic system in vivo and in vitro: identification and characterization of the conjugating enzymes. 852 78

The 26S proteasome complex plays a general role in turnover of both short and long lived proteins by specifically degrading ubiquitinated proteins. Recent evidence suggests that this large protease has more specific functions in a number of important cellular processes, ranging from activation of the transcription factor NFkB and antigen processing to transit through mitosis. We have identified a component of the 26S proteasome that interacts specifically with MB67, an orphan member of the nuclear hormone receptor superfamily. MIP224 (MB67 interacting protein) was isolated using the yeast two hybrid system and is apparently identical to the human 26S proteasome component TBP7. MIP224/TBP7 is one of several proteasomal proteins that share a strongly conserved ATPase domain (CAD) which is also present in a rapidly expanding superfamily of proteins with diverse functions. In yeast, MIP224 interacts specifically with MB67 and another closely related orphan receptor, but does not interact with several other receptor superfamily members tested. In mammalian cells, coexpression of MIP224 inhibits transactivation by MB67. MIP224 also interacts in yeast with other CAD proteins, including MSS1, which is proteasomal, and TRIP1, which is associated with transcriptional activation. This interaction of a proteasomal protein with a transcriptional protein suggests a previously unexpected link between the processes of protein degradation and transcriptional regulation.
J Steroid Biochem Mol Biol 1996 Jan
PMID:A component of the 26S proteasome binds on orphan member of the nuclear hormone receptor superfamily. 860 43

In resting T lymphocytes, the transcription factor NF-kappaB is sequestered in the cytoplasm via interactions with members of the I kappa B family of inhibitors, including IkappaBalpha and IkappaBbeta. During normal T-cell activation, IkappaBalpha is rapidly phosphorylated, ubiquitinated, and degraded by the 26S proteasome, thus permitting the release of functional NF-kappaB. In contrast to its transient pattern of nuclear induction during an immune response, NF-kappaB is constitutively activated in cells expressing the Tax transforming protein of human T-cell leukemia virus type I (HTLV-1). Recent studies indicate that HTLV-1 Tax targets IkappaBalpha to the ubiquitin-proteasome pathway. However, it remains unclear how this viral protein induces a persistent rather than transient NF-kappaB response. In this report, we provide evidence that in addition to acting on IkappaBalpha, Tax stimulates the turnover Of IkappaBbeta via a related targeting mechanism. Like IkappaBalpha, Tax-mediated breakdown of IkappaBbeta in transfected T lymphocytes is blocked either by cell-permeable proteasome inhibitors or by mutation Of IkappaBbeta at two serine residues present within its N-terminal region. Despite the dual specificity of HTLV-1 Tax for IkappaBalpha and IkappaBbeta at the protein level, Tax selectively stimulates NF-kappaB-directed transcription of the IkappaBalpha gene. Consequently, IkappaBbeta protein expression is chronically downregulated in HTLV-1-infected T lymphocytes. These findings with IkappaBbeta provide a potential mechanism for the constitutive activation of NF-kappaB in Tax-expressing cells.
Mol Cell Biol 1996 May
PMID:Inactivation of IkappaBbeta by the tax protein of human T-cell leukemia virus type 1: a potential mechanism for constitutive induction of NF-kappaB. 862 74

Transcription factor NF-kappaB is generally considered to be a heterodimer with two subunits, p50 and p65. The p50 subunit has been suggested to be generated from its precursor, p105, via the ubiquitin-proteasome pathway. During processing, the C-terminal portion of p105 is rapidly degraded whereas the N-terminal portion (p50) is left intact. We report here that a 23-amino-acid, glycine-rich region (GRR) in p105 functions as a processing signal for the generation of p50. A GRR-dependent endoproteolytic cleavage downstream of the GRR releases p50 from p105, and this cleavage does not require any specific downstream sequences. p50 can be generated from chimeric precursor p105N-GRR-IkappaBalpha, while the C-terminal portion (IkappaBalpha) can also be recovered, suggesting that p105 processing includes two steps: a GRR-dependent endoproteolytic cleavage and the subsequent degradation of the C-terminal portion. We have also demonstrated that the GRR can direct a similar processing event when it is inserted into a protein unrelated to the NF-kappaB family and that it is therefore an independent signal for processing.
Mol Cell Biol 1996 May
PMID:A glycine-rich region in NF-kappaB p105 functions as a processing signal for the generation of the p50 subunit. 862 91

NIN1 is an essential gene for growth of the yeast Saccharomyces cerevisiae and was recently found to encode a component of the regulatory subunit of the 26S proteasome. The nin1-1 mutant is temperature sensitive and its main defect is in G1/S progression and G2/M progression at non-permissive temperatures. One of the two multicopy suppressors of nin1-1, SUN2 (SUppressor of Nin1-1), was found to encode a protein of 523 amino acids whose sequence is similar to those of Drosophila melanogaster diphenol oxidase A2 and the mouse mast-cell Tum(-) transplantation antigen, P91A. The C-terminal half of Sun2p was found to be functional as Sun2p at 25 degrees C, 30 degrees C, and 34 degrees C but not at 37 degrees C. The open reading frame (ORF) of the Drosophila diphenol oxidase A2 gene (Dox-A2) was obtained from a lambda phage cDNA library using the polymerase chain reaction technique. The Dox-A2 ORF driven by the TDH3 promoter complemented the phenotype of a strain deleted for sun2. This Dox-A2-dependent strain was temperature sensitive and accumulated dumb-bell-shaped cells, with an undivided nucleus at the isthmus, after temperature upshift. This morphology is similar to that of nin1-1 cells kept at a restrictive temperature. These results suggest that SUN2 is a functional counterpart of Dox-A2 and that these genes play a pivotal role in the cell cycle in each organism.
Mol Gen Genet 1996 May 23
PMID:A multicopy suppressor of nin1-1 of the yeast Saccharomyces cerevisiae is a counterpart of the Drosophila melanogaster diphenol oxidase A2 gene, Dox-A2. 866 24

The G1 cyclin Cln3 of the yeast Saccharomyces cerevisiae is rapidly degraded by the ubiquitin-proteasome pathway. This process is triggered by p34CDC28-dependent phosphorylation of Cln3. Here we demonstrate that the molecular chaperone Ydj1, a DnaJ homolog, is required for this phosphorylation. In a ydj1 mutant at the nonpermissive temperature, both phosphorylation and degradation of Cln3 were deficient. No change was seen upon inactivation of Sis1, another DnaJ homolog. The phosphorylation defect in the ydj1 mutant was specific to Cln3, because no reduction in the phosphorylation of Cln2 or histone H1, which also requires p34CDC28, was observed. Ydj1 was required for Cln3 phosphorylation and degradation rather than for the proper folding of this cyclin, since Cln3 produced in the ydj1 mutant was fully active in the stimulation of p34CDC28 histone kinase activity. Moreover, Ydj1 directly associates with Cln3 in close proximity to the segment that is phosphorylated and signals degradation. Thus, binding of Ydj1 to this domain of Cln3 seems to be essential for the phosphorylation and breakdown of this cyclin. In a cell-free system, purified Ydj1 stimulated the p34CDC28-dependent phosphorylation of the C-terminal segment of Cln3 and did not affect phosphorylation of Cln2 (as was found in vivo). The reconstitution of this process with pure components provides evidence of a direct role for the chaperone in the phosphorylation of Cln3.
Mol Cell Biol 1996 Jul
PMID:The molecular chaperone Ydj1 is required for the p34CDC28-dependent phosphorylation of the cyclin Cln3 that signals its degradation. 866 84


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