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)

Gankyrin is a 25-kDa hepatocellular carcinoma-associated protein that mediates protein-protein interactions in cell cycle control and protein degradation. It has been reported to form complexes with cyclin-dependent kinase 4, retinoblastoma protein, the S6b ATPase subunit of the 19 S regulator of the 26 S proteasome, and Mdm2, an E3 ubiquitin ligase involved in p53 degradation. It is the first protein described to bind both to the 26 S proteasome and to proteins in other complexes containing cyclin-dependent kinase(s) and p53 ubiquitylating activities, thus providing a mechanism for delivering cell cycle regulating machinery and ubiquitylated substrates to the proteasome for degradation. Gankyrin contains a 33-residue motif known as the ankyrin repeat that occurs five and a half to six times in the sequence. As a step toward understanding gankyrin interactions with its protein partners we have determined its three-dimensional crystal structure to 2.0-A resolution. It reveals that the entire 226-residue gankyrin polypeptide folds into seven ankyrin repeat elements. The ankyrin repeats, consisting of an antiparallel beta-hairpin followed by a perpendicularly oriented helix-loop-helix, pack side-by-side, creating an extended curved structure with a groove running across the long concave surface. Comparison with the structures of other ankyrin repeat proteins suggests that interactions with partner proteins are mediated by residues situated on this concave surface.
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PMID:The crystal structure of gankyrin, an oncoprotein found in complexes with cyclin-dependent kinase 4, a 19 S proteasomal ATPase regulator, and the tumor suppressors Rb and p53. 1457 99

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.
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PMID:Feeding the machine: mechanisms of proteasome-catalyzed degradation of ubiquitinated proteins. 1458 May 55

Notch signals are important for lymphocyte development but downstream events that follow Notch signaling are not well understood. Here, we report that signaling through Notch modulates the turnover of E2A proteins including E12 and E47, which are basic helix-loop-helix proteins crucial for B and T lymphocyte development. Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. Expression of the intracellular domain of Notch1 (N1-IC) enhances the association of E47 with the SCF(Skp2) E3 ubiquitin ligase and ubiquitination of E47, followed by proteasome-mediated degradation. Furthermore, N1-IC induces E2A degradation in B and T cells in the presence of activated MAP kinases. Activation of endogenous Notch receptors by treatment of splenocytes with anti-IgM or anti-CD3 plus anti-CD28 also leads to E2A degradation, which is blocked by the inhibitors of Notch activation or proteasome function. Notch-induced E2A degradation depends on the function of its downstream effector, RBP-Jkappa, probably to activate target genes involved in the ubiquitination of E2A proteins. Thus we propose that Notch regulates lymphocyte differentiation by controlling E2A protein turnover.
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PMID:Notch-induced E2A ubiquitination and degradation are controlled by MAP kinase activities. 1459 76

Arabidopsis COP1 is a constitutive repressor of photomorphogenesis that interacts with photomorphogenesis-promoting factors such as HY5 to promote their proteasome-mediated degradation. SPA1 is a repressor of phytochrome A-mediated responses to far-red light. Here we report that COP1 acts as part of a large protein complex and interacts with SPA1 in a light-dependent manner. We further demonstrate the E3 ubiquitin ligase activity of COP1 on HY5 in vitro and the alteration of that activity by SPA1. Thus, the COP1-SPA1 interaction defines a critical step in coordinating COP1-mediated ubiquitination and subsequent degradation of HY5 with PHYA signaling.
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PMID:The COP1-SPA1 interaction defines a critical step in phytochrome A-mediated regulation of HY5 activity. 1459 62

Herpes simplex virus type 1 (HSV-1) infected cell protein 0 (ICP0) is a multifunctional protein that functions as a promiscuous transactivator and promotes the degradation of multiple cellular proteins. In vitro studies indicated that it encodes two physically separated functional E3 ubiquitin ligase domains. One, designated herpesvirus ubiquitin ligase 1 (HUL-1), maps to a region encoded by exon 3 and is contained between residues 543 and 680. Deletion of amino acids 621 to 625 abolishes this activity. The second, designated HUL-2, maps to the RING finger domain present in ICP0 encoded by exon 2. Earlier studies have shown that ICP0 stabilizes cyclins D1 and D3, and several lines of investigation led to the hypothesis that this function of ICP0 is the consequence of degradation of the E2 enzyme cdc34, known to be involved in the proteasome-dependent degradation of D-type cyclins. Consistent with this hypothesis, we have previously shown that cdc34 physically interacts with ICP0 at or near aspartate 199 and at amino acids 621 to 625 and that the former site is required for effective ubiquitylation and degradation of cdc34. Furthermore, the ICP0 HUL-1 domain promotes the polyubiquitination of cdc34 in vitro. If the mechanism by which D-type cyclins are salvaged in wild-type-infected cells is dependent on polyubiquitination and consequent destruction of cdc34, than the mutant virus R6701, which was constructed for these studies and lacks ICP0 residues 621 to 625, should destabilize the D cyclins and preclude the degradation of cdc34. We report that ICP0 residues 621 to 625 are essential for degradation of cdc34 in infected cells and for the ICP0-mediated stabilization of D-type cyclins, that a mutation that specifically disrupted the ring finger domain of the HUL-2 site had no effect on the degradation of cdc34 in infected cells, and that deletion of ICP0 residues 621 to 625 decreased the replicative capacity of the virus in growth-arrested but not in dividing cells and resulted in diminished pathogenicity on intracerebral inoculation of mice. We conclude that the ICP0 HUL-1 domain acts in infected cells to degrade cdc34 and that this function requires the interaction of cdc34 with sequences in exons 2 and 3 but does not involve the HUL-2 RING finger E3 domain.
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PMID:Herpes simplex virus 1 mutant in which the ICP0 HUL-1 E3 ubiquitin ligase site is disrupted stabilizes cdc34 but degrades D-type cyclins and exhibits diminished neurotoxicity. 1464 76

Light is an important environmental cue to plants, and much of their physiology is influenced by light. The light signals that drive these responses are perceived by photoreceptors including the red/far-red responsive phytochromes (phyA-E). In addition to direct effects, light also exerts its influence by modifying the rhythms generated by the circadian clock. In Arabidopsis thaliana, the molecular makeup of the interface between the central clock and its input/output pathways is not fully defined, but a major point of control is likely to be protein turnover mediated by the ubiquitin/26S proteasome system. To identify additional constituents of this interface, stable double-stranded RNA interference (RNAi) was used to reduce mRNA levels of rhythmically expressed candidate genes encoding putative components of E3 ubiquitin ligases (i.e., F box and RING finger proteins), followed by screening of the transgenic plants for circadian and light signaling defects. RNAi lines with diminished expression of the novel gene ATTENUATED FAR-RED RESPONSE (AFR) display phenotypes consistent with impaired phyA-mediated light signaling. Furthermore, AFR is a true SCF E3 ubiquitin ligase component. SCF(AFR) is expected to mediate the turnover of a repressor of phyA signaling, possibly to prepare the plant to receive light signals at dawn.
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PMID:The F box protein AFR is a positive regulator of phytochrome A-mediated light signaling. 1465 99

Misfolding of proteins during endoplasmic reticulum (ER) stress results in the formation of cytotoxic aggregates. The ER-associated degradation pathway counteracts such aggregation through the elimination of misfolded proteins by the ubiquitin-proteasome system. We now show that SHP substrate-1 (SHPS-1), a transmembrane glycoprotein that regulates cytoskeletal reorganization and cell-cell communication, is a physiological substrate for the Skp1-Cullin1-NFB42-Rbx1 (SCF(NFB42)) E3 ubiquitin ligase, a proposed mediator of ER-associated degradation. SCF(NFB42) mediated the polyubiquitination of immature SHPS-1 and its degradation by the proteasome. Ectopic expression of NFB42 both suppressed the formation of aggresome-like structures and the phosphorylation of the translational regulator eIF2alpha induced by overproduction of SHPS-1 as well as increased the amount of mature SHPS-1 at the cell surface. An NFB42 mutant lacking the F box domain had no such effects. Our results suggest that SCF(NFB42) regulates SHPS-1 biosynthesis in response to ER stress.
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PMID:Ubiquitination-mediated regulation of biosynthesis of the adhesion receptor SHPS-1 in response to endoplasmic reticulum stress. 1470 35

The homologue of Slimb (HOS) F-box protein is a receptor of the Skp1-Cullin1-F-box protein (SCF(HOS)) E3 ubiquitin ligase, which mediates ubiquitination and degradation of beta-catenin and the inhibitor of NFkappaB, IkappaB. We found that HOS itself is an unstable protein that undergoes ubiquitination and degradation in a 26 S proteasome-dependent manner. A HOS mutant lacking the F-box that is deficient in binding to the core SCF components underwent ubiquitination less efficiently and was more stable than the wild type protein. Furthermore, ubiquitination and degradation of HOS was impaired in ts41 cells, in which the activities of Cullin-based ligases were decreased because the NEDD8 pathway was abrogated. Whereas HOS was directly ubiquitinated within the SCF(HOS) complex in vitro, the addition of phosphorylated IkappaBalpha inhibited this ubiquitination. Increasing cellular levels of HOS substrate (phosphorylated IkappaBalpha) by activating IkappaB kinase inhibited HOS ubiquitination and led to stabilization of HOS, indicating that interaction between HOS and its substrate might protect HOS from proteolysis. Taken together, our data suggest that proteolysis of HOS depends on its interaction with active components of the SCF complex and that HOS stability is regulated by a bound substrate. These findings may define a mechanism for maintaining activities of specific SCF complexes based on availability of a particular substrate.
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PMID:Stability of homologue of Slimb F-box protein is regulated by availability of its substrate. 1470 20

The Anaphase Promoting Complex/Cyclosome (APC/C) is an E3 ubiquitin ligase that covalently attaches ubiquitins onto proteins to target them for proteolysis by the 26S proteasome. During mitosis, the APC/C is instrumental in allowing the cell to enter and exit from mitosis. The APC/C accomplishes this by using different specificity factors to recognize, interact with, and ubiquitylate key proteins that block cell cycle progression. The specificity factors, Cdc20p and Cdh1p, are not always associated with the APC/C and indeed they have the ability to interact with substrates in isolation. The molecular events that take place in order for Cdc20p and Cdh1p to couple substrates and APC/C are currently being resolved. Meanwhile, evidence has emerged suggesting that at least one of the specificity factors, Cdc20p, might be capable of functioning independently of the APC/C.
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PMID:Cdc20 in S-phase: the Banquo at replication's banquet. 1472 78

von Hippel-Lindau (VHL) tumor suppressor protein-inactivated in VHL disease and sporadic kidney cancer-is a component of an E3 ubiquitin ligase complex that selectively ubiquitinates the alpha subunit of the hypoxia-inducible factor (HIF) transcription factor for subsequent destruction by the 26S proteasome. Here, we report the identification and characterization of the first VHL homologue, VHL-like protein (VLP), located on chromosome 1q21.2. A 676-bp partial cDNA encoding a 139-amino acid protein that is 78% similar to VHL was isolated by reverse transcription-PCR from human brain cerebellum and several cancer cell lines. The expression of VLP transcript is most abundant in the placenta. Like VHL, VLP contains a beta domain capable of binding HIFalpha. However, unlike VHL, it does not contain a recognizable alpha domain, which is required for nucleating the multiprotein E3 ubiquitin ligase complex. The increased expression of VLP in the presence of VHL attenuated the ubiquitination of HIFalpha and led to the accumulation of downstream HIF target genes. These results taken together indicate that VLP functions as a dominant-negative VHL to serve as a protector of HIFalpha.
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PMID:Molecular cloning and characterization of the von Hippel-Lindau-like protein. 1475 45


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