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)

A majority of the orthopoxviruses, including the variola virus that causes the dreaded smallpox disease, encode a highly conserved 28-kDa protein with a classic RING finger sequence motif (C(3)HC(4)) at their carboxyl-terminal domains. The RING domain of p28 has been shown to be a critical determinant of viral virulence for the ectromelia virus (mousepox virus) in a murine infection model (Senkevich, T. G., Koonin, E. V., and Buller, R. M. (1994) Virology 198, 118-128). Here, we demonstrate that the p28 proteins encoded by the ectromelia virus and the variola virus possess E3 ubiquitin ligase activity in biochemical assays as well as in cultured mammalian cells. Point mutations disrupting the RING finger domain of p28 completely abolish its E3 ligase activity. In addition, p28 functions cooperatively with Ubc4 and UbcH5c, the E2 conjugating enzymes involved in 26 S proteasome degradation of protein targets. Moreover, p28 catalyzes the formation of Lys-63-linked polyubiquitin chains in the presence of Ubc13/Uev1A, a heterodimeric E2 conjugating enzyme, indicating that p28 may regulate the biological activity of its cognate viral and/or host cell target(s) by Lys-63-linked ubiquitin multimers. We thus conclude that the poxvirus p28 virulence factor is a new member of the RING finger E3 ubiquitin ligase family and has a unique polyubiquitylation activity. We propose that the E3 ligase activity of the p28 virulence factor may be targeted for therapeutic intervention against infections by the variola virus and other poxviruses.
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PMID:The poxvirus p28 virulence factor is an E3 ubiquitin ligase. 1549 20

MDM2 is an E3 ubiquitin ligase which mediates ubiquitylation and proteasome-dependent degradation of the p53 tumor suppressor protein. Phosphorylation of MDM2 by the protein kinase AKT is thought to regulate MDM2 function in response to survival signals, but there has been uncertainty concerning the identity of the sites phosphorylated by AKT. In the present study, we identify Ser-166, a site previously reported as an AKT target, and Ser-188, a novel site which is the major site of phosphorylation of MDM2 by AKT in vitro. Analysis of MDM2 in cultured cells confirms that Ser-166 and Ser-188 are phosphorylated by AKT in a physiological context.
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PMID:A novel site of AKT-mediated phosphorylation in the human MDM2 onco-protein. 1552 98

MyoD controls myoblast identity and differentiation and is required for myogenic stem cell function in adult skeletal muscle. MyoD is degraded by the ubiquitin-proteasome pathway mediated by different E3 ubiquitin ligases not identified as yet. Here we report that MyoD interacts with Atrogin-1/MAFbx (MAFbx), a striated muscle-specific E3 ubiquitin ligase dramatically up-regulated in atrophying muscle. A core LXXLL motif sequence in MyoD is necessary for binding to MAFbx. MAFbx associates with MyoD through an inverted LXXLL motif located in a series of helical leucine-charged residue-rich domains. Mutation in the LXXLL core motif represses ubiquitination and degradation of MyoD induced by MAFbx. Overexpression of MAFbx suppresses MyoD-induced differentiation and inhibits myotube formation. Finally the purified recombinant SCF(MAFbx) complex (SCF, Skp1, Cdc53/Cullin 1, F-box protein) mediated MyoD ubiquitination in vitro in a lysine-dependent pathway. Mutation of the lysine 133 in MyoD prevented its ubiquitination by the recombinant SCF(MAFbx) complex. These observations thus demonstrated that MAFbx functions in ubiquitinating MyoD via a sequence found in transcriptional coactivators. These transcriptional coactivators mediate the binding to liganded nuclear receptors. We also identified a novel protein-protein interaction module not yet identified in F-box proteins. MAFbx may play an important role in the course of muscle differentiation by determining the abundance of MyoD.
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PMID:Degradation of MyoD mediated by the SCF (MAFbx) ubiquitin ligase. 1553 60

Neuronal plasticity relies on tightly regulated control of protein levels at synapses. One mechanism to control protein abundance is the ubiquitin-proteasome degradation system. Recent studies have implicated ubiquitin-mediated protein degradation in synaptic development, function, and plasticity, but little is known about the regulatory mechanisms controlling ubiquitylation in neurons. In contrast, ubiquitylation has long been studied as a central regulator of the eukaryotic cell cycle. A critical mediator of cell-cycle transitions, the anaphase-promoting complex/cyclosome (APC/C), is an E3 ubiquitin ligase. Although the APC/C has been detected in several differentiated cell types, a functional role for the complex in postmitotic cells has been elusive. We describe a novel postmitotic role for the APC/C at Drosophila neuromuscular synapses: independent regulation of synaptic growth and synaptic transmission. In neurons, the APC/C controls synaptic size via a downstream effector Liprin-alpha; in muscles, the APC/C regulates synaptic transmission, controlling the concentration of a postsynaptic glutamate receptor.
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PMID:Independent regulation of synaptic size and activity by the anaphase-promoting complex. 1555 Feb 51

The ankyrin repeat-containing protein with a suppressor of cytokine signaling box-2 (ASB2) gene was identified as a retinoic acid-response gene and a target of the promyelocytic leukemia-retinoic acid receptor-alpha oncogenic protein characteristic of acute promyelocytic leukemia. Expression of ASB2 in myeloid leukemia cells inhibits growth and promotes commitment, recapitulating an early step known to be critical for differentiation. Here we show that ASB2, by interacting with the Elongin BC complex, can assemble with Cullin5.Rbx1 to form an E3 ubiquitin ligase complex that stimulates polyubiquitination by the E2 ubiquitin-conjugating enzyme Ubc5. This is a first indication that a member of the ASB protein family, ASB2, is a subunit of an ECS (Elongin C-Cullin-SOCS box)-type E3 ubiquitin ligase complex. Altogether, our results strongly suggest that ASB2 targets specific proteins to destruction by the proteasome in leukemia cells that have been induced to differentiate.
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PMID:ASB2 is an Elongin BC-interacting protein that can assemble with Cullin 5 and Rbx1 to reconstitute an E3 ubiquitin ligase complex. 1559 Jun 64

Loss-of-function mutations in the parkin gene, which encodes an E3 ubiquitin ligase, are the major cause of early-onset Parkinson's disease (PD). Decreases in parkin activity may also contribute to neurodegeneration in sporadic forms of PD. Here, we show that bcl-2-associated athanogene 5 (BAG5), a BAG family member, directly interacts with parkin and the chaperone Hsp70. Within this complex, BAG5 inhibits both parkin E3 ubiquitin ligase activity and Hsp70-mediated refolding of misfolded proteins. BAG5 enhances parkin sequestration within protein aggregates and mitigates parkin-dependent preservation of proteasome function. Finally, BAG5 enhances dopamine neuron death in an in vivo model of PD, whereas a mutant that inhibits BAG5 activity attenuates dopaminergic neurodegeneration. This contrasts with the antideath functions ascribed to BAG family members and suggests a potential role for BAG5 in promoting neurodegeneration in sporadic PD through its functional interactions with parkin and Hsp70.
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PMID:BAG5 inhibits parkin and enhances dopaminergic neuron degeneration. 1560 30

The ubiquitin-proteasome system is the major pathway by which cells target proteins for degradation in a specific manner. The E3 ubiquitin ligase, which brings targeted proteins (substrates) and activated ubiquitin in close proximity, enabling covalent conjugation of ubiquitin to the substrate, is an essential component of this system. Of the E3 ligases, the cullin (CUL) ligases are of high interest because of their capacity to form multiple distinct E3 complexes to ubiquitinate a potentially large number of substrates. Of the six closely related cullins, very little is known about how specific substrates are recruited to CUL4-dependent ligases. A recent paper in Nature Cell Biology may shed some light on this issue as well as on the function of DDB1, a damaged-DNA binding protein that has long been associated with DNA repair.
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PMID:Recruiting substrates to cullin 4-dependent ubiquitin ligases by DDB1. 1565 66

The p53 tumor suppressor is a transcription factor that is activated by diverse genotoxic and cytotoxic stresses. Upon activation, p53 prevents the proliferation of genetically unstable cells by regulating the expression of genes that initiate cell cycle arrest, apoptosis, and DNA repair. Consequently, p53 must be kept inactive in unstressed cells as its inappropriate activation can cause premature senescence and death. p53 inhibition occurs primarily through the E3 ubiquitin ligase, MDM2. Because MDM2 is also a p53 target gene, stresses paradoxically activate p53 while simultaneously increasing MDM2 expression. Therefore, a challenge has been to explain how the abundant MDM2 is prevented from inhibiting p53, thus ensuring that p53 can execute an appropriate stress response. Here we discuss a new mechanism for p53 activation involving DNA damage-induced auto-degradation of MDM2. Our data reveal that DNA damage leads to the destabilization of MDM2, which correlates with p53 stabilization and target gene induction. Conversely, p53 levels and activity decrease when MDM2 returns to a more stable state later in the stress response. The destabilization of MDM2 is required for p53 activation, as blocking MDM2 degradation via proteasome inhibition prevents p53 transactivation in DNA-damaged cells by enabling MDM2 to bind and inhibit p53. MDM2 destabilization is controlled by DNA damage-activated post-translational modifications and by its own RING domain, implying a possible role for the RING domain-interacting protein, MDMX, in regulating MDM2 stability. We propose that accelerated degradation of MDM2 limits its binding to p53 during a stress response and enables p53 to accumulate and remain active, even as p53 transcriptionally activates more MDM2. Thus, the induction of MDM2 RNA by activated p53 may create a reserve of MDM2 that can inactivate p53 once the DNA damage stimulus has abated and MDM2 is restabilized. As many tumors inactivate wild type p53 through MDM2 overexpression, exploiting the pathways that trigger MDM2 auto-degradation may be an important new strategy for chemotherapeutic intervention.
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PMID:A new twist in the feedback loop: stress-activated MDM2 destabilization is required for p53 activation. 1568 15

Several years have passed since NF-E2-related factor 2 (Nrf2) was demonstrated to regulate the induction of genes encoding antioxidant proteins and phase 2 detoxifying enzymes. Following a number of studies, it was realized that Nrf2 is a key factor for cytoprotection in various aspects, such as anticarcinogenicity, neuroprotection, antiinflammatory response, and so forth. These widespread functions of Nrf2 spring from the coordinated actions of various categories of target genes. The activation mechanism of Nrf2 has been studied extensively. Under normal conditions, Nrf2 localizes in the cytoplasm where it interacts with the actin binding protein, Kelch-like ECH associating protein 1 (Keap1), and is rapidly degraded by the ubiquitin-proteasome pathway. Signals from reactive oxygen species or electrophilic insults target the Nrf2-Keap1 complex, dissociating Nrf2 from Keap1. Stabilized Nrf2 then translocates to the nuclei and transactivates its target genes. Interestingly, Keap1 is now assumed to be a substrate-specific adaptor of Cul3-based E3 ubiquitin ligase. Direct participation of Keap1 in the ubiquitination and degradation of Nrf2 is plausible. The Nrf2-Keap1 system is present not only in mammals, but in fish, suggesting that its roles in cellular defense are conserved throughout evolution among vertebrates. This review article recounts recent knowledge of the Nrf2-Keap1 system, focusing especially on the molecular mechanism of Nrf2 regulation.
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PMID:Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. 1570 85

The TGF-beta superfamily signaling pathway regulates many important biological processes, including cell growth, differentiation and embryonic pattern formation. Smad1, a member of this signaling pathway that functions downstream of serine/threonine kinase receptors, has ability to interact with carboxyl terminus of Hsc70-interacting protein (CHIP), which is an E3 ubiquitin ligase in other cases. It has been reported that Smurf1, a member of the Hect family E3 ubiquitin ligases, can target Smad1 to 26S proteasome for degradation. In this paper, we studied the interaction of Smad1 and CHIP by combination of surface plasmon resonance and supported monolayer approach. The specific binding of Smad1 to CHIP indicates that the degradation of Smad1 may also be mediated by CHIP, and CHIP may play an essential role in the TGF-beta signaling pathway.
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PMID:Specific interaction between Smad1 and CHIP: a surface plasmon resonance study. 1570 1


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