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 S13 subunit (also called Pad1, Rpn11, and MPR1) is a component of the 19S complex, a regulatory complex essential for the ubiquitin-dependent proteolytic activity of the 26S proteasome. To address the functional role of S13, we combined double-stranded RNA interference (RNAi) against the Drosophila proteasome subunit DmS13 with expression of wild-type and mutant forms of the homologous human gene, HS13. These studies show that DmS13 is essential for 26S function. Loss of the S13 subunit in metazoan cells leads to increased levels of ubiquitin conjugates, cell cycle defects, DNA overreplication, and apoptosis. In vivo assays using short-lived proteasome substrates confirmed that the 26S ubiquitin-dependent degradation pathway is compromised in S13-depleted cells. In complementation experiments using Drosophila cell lines expressing HS13, wild-type HS13 was found to fully rescue the knockdown phenotype after DmS13 RNAi treatment, while an HS13 containing mutations (H113A-H115A) in the proposed isopeptidase active site was unable to rescue. A mutation within the conserved MPN/JAMM domain (C120A) abolished the ability of HS13 to rescue the Drosophila cells from apoptosis or DNA overreplication. However, the C120A mutant was found to partially restore normal levels of ubiquitin conjugates. The S13 subunit may possess multiple functions, including a deubiquitinylating activity and distinct activities essential for cell cycle progression that require the conserved C120 residue.
...
PMID:Use of RNA interference and complementation to study the function of the Drosophila and human 26S proteasome subunit S13. 1286 Oct 18

The proteasome plays a role in a myriad of intracellular processes from cell-cycle control to antigen presentation. Central to these processes is the targeting of selected proteins for proteasomal degradation via their conjugation to ubiquitin. The mechanisms by which the ubiquitin-dependent proteasomal proteolysis occurs can be divided into four steps: first, substrate protein recognition by its cognate E3 ubiquitin ligase; second, polyubiquitinated protein substrate recruitment to the proteasome; third, protein substrate deubiquitination; and four, proteolytic chamber pore opening/substrate translocation followed by proteolysis. Recent advances include the identification of novel E3 ubiquitin ligase recognition determinants, a new isopeptidase activity, and a better understanding of how the proteasome's axial channels are gated.
...
PMID:Feeding the machine: mechanisms of proteasome-catalyzed degradation of ubiquitinated proteins. 1458 May 55

The JAMM (JAB1/MPN/Mov34 metalloenzyme) motif in Rpn11 and Csn5 underlies isopeptidase activities intrinsic to the proteasome and signalosome, respectively. We show here that the archaebacterial protein AfJAMM possesses the key features of a zinc metalloprotease, yet with a distinct fold. The histidine and aspartic acid of the conserved EX(n)HS/THX(7)SXXD motif coordinate a zinc, whereas the glutamic acid hydrogen-bonds an aqua ligand. By analogy to the active site of thermolysin, we predict that the glutamic acid serves as an acid-base catalyst and the second serine stabilizes a tetrahedral intermediate. Mutagenesis of Csn5 confirms these residues are required for Nedd8 isopeptidase activity. The active site-like architecture specified by the JAMM motif motivates structure-based approaches to the study of JAMM domain proteins and the development of therapeutic proteasome and signalosome inhibitors.
...
PMID:JAMM: a metalloprotease-like zinc site in the proteasome and signalosome. 1473 82

NEDD8 is a ubiquitin-like protein that controls vital biological events through its conjugation to target proteins. Previously, we identified a negative regulator of the NEDD8 conjugation system, NEDD8 ultimate buster-1 (NUB1), that recruits NEDD8 and its conjugates to the proteasome for degradation. Recently, we performed yeast two-hybrid screening with NUB1 as bait and isolated a ubiquitin precursor UbC1 that is composed of nine tandem repeats of a ubiquitin unit through alpha-peptide bonds. Interestingly, NUB1 interacted with UbC1 through its UBA domain. Further study revealed that the UBA domain interacted with alpha-peptide bond-linked polyubiquitin, but not with isopeptide bond-linked polyubiquitin, indicating that the UBA domain of NUB1 is a specific acceptor for the linear ubiquitin precursor. A functional study revealed that an unidentified protein that was immunoprecipitated with NUB1 served as a ubiquitin C-terminal hydrolase for UbC1. Thus, NUB1 seems to form a protein complex with the unidentified ubiquitin C-terminal hydrolase and recruit UbC1 to this complex. This might allow the ubiquitin C-terminal hydrolase to hydrolyze UbC1, in order to generate ubiquitin monomers. Northern blot analysis showed that the mRNAs of both NUB1 and UbC1 were enriched in the testis. Furthermore, in situ hybridization showed that both mRNAs were strongly expressed in seminiferous tubules of the testis. These results may imply that the UbC1 hydrolysis mediated by NUB1 is involved in cellular functions in the seminiferous tubules such as spermatogenesis.
...
PMID:NUB1-mediated targeting of the ubiquitin precursor UbC1 for its C-terminal hydrolysis. 1500 9

Cyclopentenone prostaglandins exhibit unique antineoplastic activity and are potent growth inhibitors in a variety of cultured cells. Recently the dienone prostaglandin, Delta(12)-PGJ(2), was shown to preferentially inhibit ubiquitin isopeptidase activity of the proteasome pathway. It is theorized that isopeptidase inhibition and general cytotoxicity of prostaglandins depend on olefin-ketone conjugation, electrophilic accessibility, and the nucleophilic reactivity of the endocyclic beta-carbon. Delta(12)-PGJ(2), which contains a cross-conjugated alpha,beta-unsaturated ketone, was a potent inhibitor of isopeptidase activity, whereas PGA(1) and PGA(2) with simple alpha,beta-unsaturated pentenones were significantly less potent and PGB(1) with a sterically hindered alpha,beta-unsaturated ketone was inactive. To further investigate the proposed mechanism, punaglandins, which are highly functional cyclopentadienone and cyclopentenone prostaglandins chlorinated at the endocyclic alpha-carbon position, were isolated from the soft coral Telesto riisei. They were then assayed for inhibition of ubiquitin isopeptidase activity and antineoplastic effects. The punaglandins were shown to inhibit isopeptidase activity and exhibit antiproliferative effects more potently than A and J series prostaglandins. Also, the cross-conjugated dienone punaglandin was more potent than the simple enone punaglandin. The ubiquitin-proteasome pathway is a vital component of cellular metabolism and may be a suitable target for antineoplastic agents. These newly characterized proteasome inhibitors may represent a new chemical class of cancer therapeutics.
...
PMID:Punaglandins, chlorinated prostaglandins, function as potent Michael receptors to inhibit ubiquitin isopeptidase activity. 1505 3

The ubiquitin/proteasome pathway for degradation of completed and nascent globin chains was evaluated using a cell-free in vitro coupled transcription/translation assay. No decrease in radiolabeled globin chains was observed when ubiquitin, energy regenerating source (or ATP), and E1 and E2 enzymes were added 30 min after the start of translation when globin chain synthesis had plateaued. In contrast, the addition of these components prior to the start of translation resulted in no radiolabeled globin chains after 30 min. The loss of radiolabeled globin chains was dependent on ATP concentration; the higher the concentration, the less the radiolabeled globin chains formed. Prior to the initiation of transcription/translation, cell extract was preincubated with the proteasomal inhibitor MG132 in the absence of globin chain expression vector after which ubiquitin-protein isopeptidase inhibitor, Ubal, and expression vector were added in the presence of 1.5 mm ATP. Thereafter, radiolabeled monoubiquitylated and multiubiquitylated globin chains with few unmodified globin chains were formed. Our results suggest that polyubiquitylated globin chains are localized to the polysomal fractions. These results suggest that nascent globin chains are potential targets for ubiquitylation and deubiquitylation during or soon after translation and that ATP levels play a role in the balance between polypeptide synthesis and degradation.
...
PMID:Ubiquitylation of nascent globin chains in a cell-free system. 1529 54

The JAMM (JAB1/MPN/Mov34 metalloenzyme) motif has been proposed to provide the active site for isopeptidase activity associated with the Rpn11/POH1 subunit of the 19S-proteasome and the Csn5-subunit of the signalosome. We have looked for similar activity in associated molecule with the SH3 domain of STAM (AMSH), a JAMM domain-containing protein that associates with the SH3-domain of STAM, a protein, which regulates receptor sorting at the endosome. We demonstrate isopeptidase activity against K48-linked tetraubiquitin and K63-linked polyubiquitin chains to generate di-ubiquitin and free ubiquitin, respectively. An inactivating mutation (D348A) in AMSH leads to accumulation of ubiquitin on endosomes and the concomitant stabilization of a ubiquitinated form of STAM, which requires an intact ubiquitin interaction motif (UIM) within STAM. Short interfering RNA knockdown of AMSH enhances the degradation rate of EGF receptor (EGFR) following acute stimulation and ubiquitinated EGFR provides a substrate for AMSH in vitro. We propose that AMSH is a deubiquitinating enzyme with functions at the endosome, which oppose the ubiquitin-dependent sorting of receptors to lysosomes.
...
PMID:AMSH is an endosome-associated ubiquitin isopeptidase. 1531 65

The experimentally induced cryptorchid mouse model is useful for elucidating the in vivo molecular mechanism of germ cell apoptosis. Apoptosis, in general, is thought to be partly regulated by the ubiquitin-proteasome system. Here, we analyzed the function of two closely related members of the ubiquitin C-terminal hydrolase (UCH) family in testicular germ cell apoptosis experimentally induced by cryptorchidism. The two enzymes, UCH-L1 and UCH-L3, deubiquitinate ubiquitin-protein conjugates and control the cellular balance of ubiquitin. The testes of gracile axonal dystrophy (gad) mice, which lack UCH-L1, were resistant to cryptorchid stress-related injury and had reduced ubiquitin levels. The level of both anti-apoptotic (Bcl-2 family and XIAP) and prosurvival (pCREB and BDNF) proteins was significantly higher in gad mice after cryptorchid stress. In contrast, Uchl3 knockout mice showed profound testicular atrophy and apoptotic germ cell loss after cryptorchid injury. Ubiquitin level was not significantly different between wild-type and Uchl3 knockout mice, whereas the levels of Nedd8 and the apoptotic proteins p53, Bax, and caspase3 were elevated in Uchl3 knockout mice. These results demonstrate that UCH-L1 and UCH-L3 function differentially to regulate the cellular levels of anti-apoptotic, prosurvival, and apoptotic proteins during testicular germ cell apoptosis.
...
PMID:Two closely related ubiquitin C-terminal hydrolase isozymes function as reciprocal modulators of germ cell apoptosis in cryptorchid testis. 1546

The COP9 signalosome (CSN) is a multiprotein complex of the ubiquitin-proteasome pathway. CSN is typically composed of eight subunits, each of which is related to one of the eight subunits that form the lid of the 26S proteasome regulatory particle. CSN was first identified in Arabidopsis where it is required for the repression of photomorphogenic seedling development in the dark. CSN or CSN-related complexes have by now been reported from most eukaryotic model organisms and CSN has been implicated in a vast array of biological processes. It is widely accepted that CSN directly interacts with cullin-containing E3 ubiquitin ligases, and that CSN is required for their proper function. The requirement of CSN for proper E3 function may at least in part be explained by the observation that CSN subunit 5 (CSN5) is the isopeptidase that deconjugates the essential ubiquitin-like Nedd8 modification from the E3 cullin subunit. In addition to its interaction with E3s, CSN may also regulate proteolysis by its association with protein kinases and deubiquitylating enzymes. This review provides a summary of the role of CSN in regulating protein degradation and in eukaryotic development.
...
PMID:The COP9 signalosome (CSN): an evolutionary conserved proteolysis regulator in eukaryotic development. 1557 8

Parkinson's disease (PD) is a multifactorial disease that appears to arise from the effects of both genetic and environmental influences. Pesticides and heavy metals are the principle environmental factors that appear to impact on PD. The known genetic factors include multiple genes that have been identified in related parkinsonian syndromes, as well as alpha-synuclein. Genes associated with either PD or Parkinson-related disorders include parkin, DJ-1, ubiquitin C-terminal hydrolase isozyme L1 (UCH-L1), nuclear receptor-related factor 1, and alpha-synuclein. Alpha-synuclein is particularly notable because it aggregates readily and is the main component of Lewy bodies (LBs). Aggregated alpha-synuclein binds the proteasome and potently inhibits proteasomal activity. Because ubiquitin accumulates in LBs, and parkin and UCH-L1 also interact with the ubiquitin proteasomal system, proteasomal dysfunction is thought to contribute to the pathophysiology of PD. Increasing numbers of experiments suggest that neurotoxins might interact with alpha-synuclein or other Parkinson-related proteins to contribute to the pathophysiology of PD. Transgenic animal models overexpressing alpha-synuclein develop age-dependent motor dysfunction and inclusions in the brain stem that contain alpha-synuclein. These models are very helpful in elucidating the pathophysiology of PD but do not completely recapitulate the disease process. The relationship between these transgenic models and PD is a subject of intense investigation.
...
PMID:Pathological proteins in Parkinson's disease: focus on the proteasome. 1565 64


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

---