Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein degradation is an essential mechanism for the maintenance of cellular homeostasis, in which excess or aberrant proteins are eliminated from the cell. In eukaryotes, conjugation of target proteins to ubiquitin is an essential step in the proteasome-dependent degradation process and is mediated by a family of ubiquitin conjugating enzymes (UBC). Several of these have been identified in a variety of organisms. Here we report the identification of UBE2G2, a human homologue of the yeast Ubc7 gene. We describe a 2.9-kb cDNA sequence encoding a 165-amino-acid protein that shares significant similarity with other members of the UBC family. We have found UBE2G2 to be ubiquitously expressed, with high levels of expression seen in adult muscle, and have detected two transcripts of 2.9 and 7.0 kb in all tissues. In addition, we have mapped UBC7 to human chromosome 21q22.3 close to 21qtel.
 ...
PMID:Identification, expression, and chromosomal localization of ubiquitin conjugating enzyme 7 (UBE2G2), a human homologue of the Saccharomyces cerevisiae ubc7 gene. 969 41

The endoplasmic reticulum quality control (ERQC) system retains and degrades soluble and membrane proteins that misfold or fail to assemble. Vph1p is the 100 kDa membrane subunit of the yeast Saccharomyces cerevisiae V-ATPase, which together with other subunits, assembles into the V-ATPase in the ER, requiring the ER resident protein Vma22p. In vma22Delta cells, Vph1p remains an integral membrane protein with wild-type topology in the ER membrane before undergoing a rapid and concerted degradation requiring neither vacuolar proteases nor transport to the Golgi. Failure to assemble targets Vph1p for degradation in a process involving ubiquitylation, the proteasome and cytosolic but not ER lumenal chaperones. Vph1p appears to possess the traits of a 'classical' ERQC substrate, yet novel characteristics are involved in its degradation: (i) UBC genes other than UBC6 and UBC7 are involved and (ii) components of the ERQC system identified to date (Der1p, Hrd1p/Der3p and Hrd3p) are not required. These data suggest that other ERQC components must exist to effect the degradation of Vph1p, perhaps comprising an alternative pathway.
 ...
PMID:Degradation of unassembled Vph1p reveals novel aspects of the yeast ER quality control system. 1067 24

Cytochrome P450, CYP3A4, is the dominant human liver endoplasmic reticulum (ER) hemoprotein enzyme, responsible for the metabolism of over 60% of clinically relevant drugs. We have previously shown that mechanism-based suicide inactivation of CYP3A4 and its rat liver ER orthologs, CYPs 3A, via heme-modification of their protein moieties, results in their ubiquitin (Ub)-dependent 26S proteasomal degradation (Korsmeyer et al. (1999) Arch. Biochem. Biophys. 365, 31; Wang et al. (1999) Arch. Biochem. Biophys. 365, 45). This is not surprising given that the heme-modified CYP3A proteins are structurally damaged. To determine whether the turnover of the native enzyme similarly recruited this pathway, we heterologously expressed this protein in wild-type Saccharomyces cerevisiae and mutant strains (hrd1Delta, hrd2-1, and hrd3Delta) previously shown to be deficient in the Ub-dependent 26S proteasomal degradation of the polytopic ER protein 3-hydroxy-3-methylglutaryl-CoA reductase (isoform Hmg2p), the rate-limiting enzyme in sterol biosynthesis, as well as in strains deficient in ER-associated Ub-conjugating enzymes, Ubc6p and/or Ubc7p (Hampton et al. (1996) Mol. Biol. Cell 7, 2029; Hampton and Bhakta (1997) Proc. Natl. Acad. Sci. USA 94, 12,944). Our findings reveal that in common with the degradation of Hmg2p, that of native CYP3A4 also requires Hrd2p (a subunit of the 19S cap complex of the 26S proteasome) and Ubc7p, and to a much lesser extent Hrd3p, a component of the ER-associated Ub-ligase complex. In contrast to Hmg2p-degradation, that of native CYP3A4 does not appear to absolutely require Hrd1p, another component of the ER-associated Ub-ligase complex. Furthermore, studies in a S. cerevisiae pep4Delta strain proven to be deficient in the vacuolar degradation of carboxypeptidase Y indicated that CYP3A4 degradation is also largely independent of vacuolar (lysosomal) proteolytic function. The degradation of two other native ER proteins, Sec61p and Sec63p, normal components of the ER translocon, were also examined in parallel and found to be stabilized to some extent in HRD2- and UBC7-deficient strains. Together these findings attest to the remarkable mechanistic diversity in the normal degradation of ER proteins.
 ...
PMID:Ubiquitin-dependent 26S proteasomal pathway: a role in the degradation of native human liver CYP3A4 expressed in Saccharomyces cerevisiae? 1151 67

Mutation of either the yeast MPS2 or the NDC1 gene leads to identical spindle pole body (SPB) duplication defects: The newly formed SPB is improperly inserted into the nuclear envelope (NE), preventing the cell from forming a bipolar mitotic spindle. We have previously shown that both MPS2 and NDC1 encode integral membrane proteins localized at the SPB. Here we show that CUE1, previously known to have a role in coupling ubiquitin conjugation to ER degradation, is an unusual dosage suppressor of mutations in MPS2 and NDC1. Cue1p has been shown to recruit the soluble ubiquitin-conjugating enzyme, Ubc7p, to the cytoplasmic face of the ER membrane where it can ubiquitinate its substrates and target them for degradation by the proteasome. Both mps2-1 and ndc1-1 are also suppressed by disruption of UBC7 or its partner, UBC6. The Mps2-1p mutant protein level is markedly reduced compared to wild-type Mps2p, and deletion of CUE1 restores the level of Mps2-1p to nearly wild-type levels. Our data indicate that Mps2p may be targeted for degradation by the ER quality control pathway.
 ...
PMID:Mutant membrane protein of the budding yeast spindle pole body is targeted to the endoplasmic reticulum degradation pathway. 1239 72

Ubiquitination of membrane-associated proteins can direct their proteasome-mediated degradation or activation at the endoplasmic reticulum (ER), as well as their endocytosis and intracellular sorting. However, the full spectrum of ubiquitinated membrane proteins has not been determined. Here we combined proteomic analysis with yeast genetics to identify 211 ubiquitinated membrane-associated proteins in Saccharomyces cerevisiae and map >30 precise sites of ubiquitination. Major classes of identified ubiquitinated proteins include ER-resident membrane proteins, plasma membrane-localized permeases, receptors, and enzymes, and surprisingly, components of the actin cytoskeleton. By determining the differential abundance of ubiquitinated proteins in yeast mutated for NPL4 and UBC7, which are major components of ER-associated degradation (ERAD), we furthermore were able to classify 83 of these identified ubiquitinated membrane proteins as potential endogenous substrates of the ERAD pathway. These substrates are highly enriched for proteins that localize to or transit through the ER. Interestingly, we also identified novel membrane-bound transcription factors that may be subject to ubiquitin/proteasome-mediated cleavage and activation at the ER membrane.
 ...
PMID:A subset of membrane-associated proteins is ubiquitinated in response to mutations in the endoplasmic reticulum degradation machinery. 1455 38

In the present study, the human TEB4 is identified as a novel ER (endoplasmic reticulum)-resident ubiquitin ligase. TEB4 has homologues in many species and has a number of remarkable properties. TEB4 contains a conserved RING (really interesting new gene) finger and 13 predicted transmembrane domains. The RING finger of TEB4 and its homologues is situated at the N-terminus and has the unconventional C4HC3 configuration. The N-terminus of TEB4 is located in the cytosol. We show that the isolated TEB4 RING domain catalyses ubiquitin ligation in vitro in a reaction that is ubiquitin Lys48-specific and involves UBC7 (ubiquitin-conjugating enzyme 7). These properties are reminiscent of E3 enzymes, which are involved in ER-associated protein degradation. TEB4 is an ER degradation substrate itself, promoting its own degradation in a RING finger- and proteasome-dependent manner.
 ...
PMID:TEB4 is a C4HC3 RING finger-containing ubiquitin ligase of the endoplasmic reticulum. 1567 84

Serum- and glucocorticoid-induced kinase 1 (Sgk1) regulates many ion channels and transporters in epithelial cells and promotes cell survival under stress conditions. In this study we demonstrate that Sgk1 is a short-lived protein regulated by the endoplasmic reticulum (ER)-associated degradation system and subcellular localization to the ER. We identified a hydrophobic motif (residues 18-30) as the signal for ER localization and rapid degradation by the ubiquitin (Ub)/proteasome pathway in both yeast and mammalian cells. Deletion or reduction of hydrophobicity of the motif redistributes Sgk1 to the cytosol and nucleus and markedly increases its half-life. We determined that the Ub-conjugating UBC6 and UBC7 and the Ub ligase HRD1 are the ER-associated Ub enzymes that mediate degradation of Sgk1; thus, Sgk1 has been identified as a cytosolic substrate for mammalian HRD1. Compartmentalization of Sgk1 controls the functional and spatial specificities of Sgk1-mediated signaling pathways, whereas rapid protein turnover provides a means to rapidly adjust Sgk1 abundance in response to different hormonal and external stimuli that increase Sgk1 gene transcription.
 ...
PMID:An amphipathic helix targets serum and glucocorticoid-induced kinase 1 to the endoplasmic reticulum-associated ubiquitin-conjugation machinery. 1684 54