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)

TSC1 (tuberous sclerosis complex 1) encoding hamartin and TSC2 encoding tuberin are tumor suppressor genes responsible for the autosomal dominantly inherited disease tuberous sclerosis. These genes have been demonstrated to negatively regulate cell cycle progression, the activity of cdk2, and the degradation of the cyclin-dependent kinase inhibitor p27. To date, the underlying molecular mechanism remains elusive. Here, we show that tuberin binds to p27. Whereas tuberin also binds p27 in TSC1-negative cells, hamartin does not bind p27 without tuberin. p27 protein levels are regulated through ubiquitin-dependent degradation. Skp2 is the F-box protein, which, together with other proteins, forms an SCF (Skp1/cullin/F-box protein)-type E3 ubiquitin ligase complex whose task is to target p27 for degradation by the proteasome. We found that neither tuberin nor hamartin are in a complex with Skp2. Tuberin does not affect Skp2 protein levels, and the SCFSkp2 ubiquitin ligase does not regulate tuberin stability. But binding of tuberin to p27 sequesters p27 from Skp2 accompanied by an up-regulation of the p27 interaction with cdk2. Skp2-induced p27 degradation and cell cycle progression is abolished by tuberin's protective binding to p27. This work, the first description of the direct interaction of a tumor suppressor protein with p27, provides a molecular explanation for the effects of tuberous sclerosis complex genes on the cell cycle and demonstrates a new aspect of the SCFSkp2-mediated regulation of p27 stability.
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PMID:Tuberin binds p27 and negatively regulates its interaction with the SCF component Skp2. 1535 97

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

Mitochondria form a highly dynamic network that is shaped by continuous fission and fusion of these organelles. In the yeast Saccharomyces cerevisiae two machineries are involved in this process, one of which includes the mitochondrial fusion promoting GTPase Fzo1. Although a role for the F-box protein Mdm30 in regulating the stability of Fzo1 has been proposed, the molecular basis for the regulation of the fission to fusion ratio of mitochondria remains unknown. To discern the mechanism of the regulation of mitochondrial morphology, we arrested cells at different stages of the cell cycle and examined mitochondrial morphology as well as the stability of mitochondrial fission and fusion proteins. In response to a G1 arrest evoked by the mating pheromone alpha factor the mitochondrial network fragmented into small pieces, which was accompanied by dramatic down-regulation of Fzo1. Mating pheromone also triggered the degradation of Fzo1 produced under the control of a constitutive promoter, and Fzo1 was stabilized upon proteasome inhibition, indicating a role for the proteasome system in the degradation of Fzo1. However, deletion of MDM30 did not stabilize Fzo1 after mating pheromone treatment, showing a different mechanism from the previously reported process of steady state Fzo1 regulation. We show an example for a regulated change of the mitochondrial fission to fusion ratio during the life cycle of budding yeast. Proteasomal degradation of Fzo1 in response to the mating pheromone is proposed to mediate the remodeling of the mitochondrial network during the process of mating.
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PMID:Instability of the mitofusin Fzo1 regulates mitochondrial morphology during the mating response of the yeast Saccharomyces cerevisiae. 1576 Aug 98

Cullin-based E3 ubiquitin ligases play important roles in the regulation of diverse developmental processes and environmental responses in eukaryotic organisms. Recently, it was shown in Schizosaccharomyces pombe, Caenorhabditis elegans, and mammals that Cullin3 (CUL3) directly associates with RBX1 and BTB domain proteins in vivo to form a new family of E3 ligases, with the BTB protein subunit functioning in substrate recognition. Here, we demonstrate that Arabidopsis thaliana has two redundant CUL3 (AtCUL3) genes that are essential for embryo development. Besides supporting anticipated specific AtCUL3 interactions with the RING protein AtRBX1 and representative Arabidopsis proteins containing a BTB domain in vitro, we show that AtCUL3 cofractionates and specifically associates with AtRBX1 and a representative BTB protein in vivo. Similar to the AtCUL1 subunit of the SKP1-CUL1-F-box protein-type E3 ligases, the AtCUL3 subunit of the BTB-containing E3 ligase complexes is subjected to modification and possible regulation by the ubiquitin-like protein Related to Ubiquitin in vivo. Together with the presence of large numbers of BTB proteins with diverse structural features and expression patterns, our data suggest that Arabidopsis has conserved AtCUL3-RBX1-BTB protein E3 ubiquitin ligases to target diverse protein substrates for degradation by the ubiquitin/proteasome pathway.
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PMID:Arabidopsis has two redundant Cullin3 proteins that are essential for embryo development and that interact with RBX1 and BTB proteins to form multisubunit E3 ubiquitin ligase complexes in vivo. 1577 80

SCF-type (SCF: Skp1-Cullin-F-box protein complex) E3 ligases regulate ubiquitin-dependent degradation of many cell cycle regulators, mainly at the G1/S transition. Here, we show that SCF(Grr1) functions during cytokinesis by degrading the PCH protein Hof1. While Hof1 is required early in mitosis to assemble a functional actomyosin ring, it is specifically degraded late in mitosis and remains unstable during the entire G1 phase of the cell cycle. Degradation of Hof1 depends on its PEST motif and a functional 26S proteasome. Interestingly, degradation of Hof1 is independent of APC(Cdh1), but instead requires the SCF(Grr1) E3 ligase. Grr1 is recruited to the mother-bud neck region after activation of the mitotic-exit network, and interacts with Hof1 in a PEST motif-dependent manner. Our results also show that downregulation of Hof1 at the end of mitosis is necessary to allow efficient contraction of the actomyosin ring and cell separation during cytokinesis. SCF(Grr1)-mediated degradation of Hof1 may thus represent a novel mechanism to couple exit from mitosis with initiation of cytokinesis.
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PMID:Degradation of Hof1 by SCF(Grr1) is important for actomyosin contraction during cytokinesis in yeast. 1577 61

The extracellular N-terminal domain (NTD) is the largest region of NMDA receptors; however, biological roles for this ectodomain remain unknown. Here, we determined that the F-box protein, Fbx2, bound to high-mannose glycans of the NR1 ectodomain. F-box proteins specify ubiquitination by linking protein substrates to the terminal E3 ligase. Indeed, ubiquitination of NR1 was increased by Fbx2 and diminished by an Fbx2 dominant-negative mutant. When expressed in hippocampal neurons, this Fbx2 dominant-negative mutant augmented NR1 subunit levels and NMDA receptor-mediated currents in an activity-dependent fashion. These results suggest that homeostatic control of synaptic NR1 involves receptor retrotranslocation and degradation by the ubiquitin-proteasome pathway.
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PMID:Activity-dependent NMDA receptor degradation mediated by retrotranslocation and ubiquitination. 1580 37

Substrate-specific degradation of proteins by the ubiquitin-proteasome pathway is a precise mechanism that controls the abundance of key cell regulators. SCF complexes are a family of E3 ubiquitin ligases that target specific proteins for destruction at the 26S-proteasome. These complexes are composed of three constant polypeptides--Skp1, Cullin1/3 and Roc1/Rbx1--and a fourth variable adapter, the F-box protein. Slimb (Slmb) is a Drosophila F-Box protein that fulfills several roles in development and cell physiology. We analyzed its participation in egg chamber development and found that slmb is required in both the follicle cells and the germline at different stages of oogenesis. We observed that in slmb somatic clones, morphogenesis of the germarium and encapsulation of the cyst were altered, giving rise to egg chambers with extra germline cells and two oocytes. Furthermore, in slmb somatic clones, we observed ectopic Fasciclin 3 expression, suggesting a delay in follicle cell differentiation, which correlated with the occurrence of ectopic polar cells, lack of interfollicular stalks and mislocalization of the oocyte. Later in oogenesis, Slmb was required in somatic cells to specify the position, size and morphology of dorsal appendages. Mild overactivation of the Dpp pathway caused similar phenotypes that could be antagonized by simultaneous overexpression of Slmb, suggesting that Slmb might normally downregulate the Dpp pathway in follicle cells. Indeed, ectopic expression of a dad-LacZ enhancer trap revealed that the Dpp pathway was upregulated in slmb somatic clones and, consistent with this, ectopic accumulation of the co-Smad protein, Medea, was recorded. By analyzing slmb germline clones, we found that loss of Slmb provoked a reduction in E2f2 and Dp levels, which correlated with misregulation of mitotic cycles during cyst formation, abnormal nurse cell endoreplication and impairment of dumping of the nurse cell content into the oocyte.
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PMID:Multiple roles of the F-box protein Slimb in Drosophila egg chamber development. 1585 15

The SCF family of ubiquitin-ligases consists of a common core machinery, namelySkp1p, Cdc53p, Hrt1p, and a variable component, the F-box protein that is responsible for substrate recognition. The F-box motif, which consists of approximately 40 amino acids, connects the F-box protein to the core ubiquitin-ligase machinery. Distinct SCF complexes, defined by distinct F-box proteins, target different substrate proteins for proteasome-dependent degradation. As part of the SCF(Met30p) complex, the F-box protein Met30p selects the substrate Met4p, a transcriptional activator for MET biosynthetic genes that mediate sulfur uptake and biosynthesis of sulfur containing compounds. When cells are grown in the absence of methionine, Met4p evades degradation by the SCF(Met30p) complex and activates the MET biosynthetic pathway. However, overproduction of Met30p represses MET gene expression and induces methionine auxotrophy in an otherwise methionine prototrophic strain. Here we demonstrate that overproduction of the C-terminal portion of Met30p, which is composed almost entirely of seven WD-40 repeat motifs, is necessary and sufficient to induce methionine auxotrophy and complement the temperature sensitive (ts) met30-6 mutation. Furthermore, we show that this region of Met30p is important for binding Met4p and that mutations that disrupt this interaction prevent both the induction of methionine auxotrophy and complementation of the met30-6 mutation. These assays have been exploited to identify residues that are important for the interaction of Met30p with its substrate. Since the C-terminal domain of Met30p lacks the F-box and cannot support the ubiquitination of Met4p, our results indicate that the recruitment of Met4p to the SCF(Met30p) complex itself results in inactivation of Met4p, independently of its ubiquitination.
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PMID:Identification of residues in the WD-40 repeat motif of the F-box protein Met30p required for interaction with its substrate Met4p. 1588 25

beta-TrCP is the F-box protein component of an Skp1/Cul1/F-box (SCF)-type ubiquitin ligase complex. Biochemical studies have suggested that beta-TrCP targets the oncogenic protein beta-catenin for ubiquitination and followed by proteasome degradation. To further elucidate the basis of this interaction, a complex between a 32-residue peptide from beta-catenin containing the phosphorylated motif DpSGXXpS (P-beta-Cat17-48) and beta-TrCP was studied using Saturation Transfer Difference (STD) Nuclear Magnetic Resonance (NMR) experiments. These experiments make it possible to identify the binding epitope of a ligand at atomic resolution. An analysis of STD spectra provided clear evidence that only a few of the 32 residues receive the largest saturation transfer. In particular, the amide protons of the residues in the phosphorylated motif appear to be in close contact to the amino acids of the beta-TrCP binding pocket. The amide and aromatic protons of the His24 and Trp25 residues also receive a significant saturation transfer. These findings are in keeping with a recently published x-ray structure of a shorter beta-catenin fragment with the beta-TrCP1-Skp1 complex and with the earlier findings from mutagenesis and activity assays. To better characterize the ligand-protein interaction, the bound conformation of the phosphorylated beta-catenin peptide was obtained using TRansfer Nuclear Overhauser Effect SpectroscopY (TRNOESY) experiments. Finally, we obtained the bound structure of the phosphorylated peptide showing the protons identified by STD NMR as exposed in close proximity to the molecule surface.
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PMID:STD and TRNOESY NMR studies on the conformation of the oncogenic protein beta-catenin containing the phosphorylated motif DpSGXXpS bound to the beta-TrCP protein. 1592 56

Ho endonuclease initiates a mating type switch by making a double-strand break at the mating type locus, MAT. Ho is marked by phosphorylation for rapid destruction by functions of the DNA damage response, MEC1, RAD9, and CHK1. Phosphorylated Ho is recruited for ubiquitylation via the SCF ubiquitin ligase complex by the F-box protein, Ufo1. Here we identify a further DNA damage-inducible protein, the UbL-UbA protein Ddi1, specifically required for Ho degradation. Ho interacts only with Ddi1; it does not interact with the other UbL-UbA proteins, Rad23 or Dsk2. Ho must be ubiquitylated to interact with Ddi1, and there is no interaction when Ho is produced in mec1 or Deltaufo1 mutants that do not support its degradation. Ddi1 binds the proteasome via its N-terminal ubiquitin-like domain (UbL) and interacts with ubiquitylated Ho via its ubiquitin-associated domain (UbA); both domains of Ddi1 are required for association of ubiquitylated Ho with the proteasome. Despite being a nuclear protein, Ho is exported to the cytoplasm for degradation. In the absence of Ddi1, ubiquitylated Ho is stabilized and accumulates in the cytoplasm. These results establish a role for Ddi1 in the degradation of a natural ubiquitylated substrate. The specific interaction between Ho and Ddi1 identifies an additional function associated with DNA damage involved in its degradation.
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PMID:The DNA damage-inducible UbL-UbA protein Ddi1 participates in Mec1-mediated degradation of Ho endonuclease. 1596 93


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