Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A gene (eft-1) encoding an elongation factor 2-like protein was isolated from a region adjacent to the polyubiquitin gene, ubq-1, of Caenorhabditis elegans. Sequence analysis of genomic and cDNA clones revealed that the deduced amino acid sequence of the protein (EFT-1) is 38% identical to that of mammalian and Drosophila elongation factor 2 (EF-2). The entire eft-1 gene is approximately 3.8 kb in length and contains 5 exons separated by short introns of 46-75 bp. The 2,547-bp open reading frame predicts a protein of 849 amino acid residues (calculated Mr, 96,151). Conserved sequences shared among a variety of GTP-binding proteins including EF-2 are found in the amino-terminal third of EFT-1. The carboxy-terminal half contains regions with 40-57% similarity (including conservative changes) with segments characteristic of EF-2 and its prokaryotic homolog, EF-G. However, the histidyl residue target for ADP-ribosylation of EF-2 by diphtheria toxin is replaced by tyrosine in EFT-1. Southern and Northern blot analyses indicate that eft-1 is a single-copy gene that is expressed at all stages of nematode development. Amplification of fragments encoding highly conserved regions of EF-2 using the polymerase chain reaction led to the isolation of a fragment encoding the modifiable histidyl residue and which likely represents part of the C. elegans EF-2 gene (eft-2). This suggests that EFT-1 is not the C. elegans homolog of EF-2, but a closely related protein.
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PMID:Isolation and characterization of eft-1, an elongation factor 2-like gene on chromosome III of Caenorhabditis elegans. 173 35

We have investigated three aspects of nucleotide usage by the 26S proteasome and its regulatory complex (RC). Both particles hydrolyze the four major ribonucleotides, but ATP and CTP have substantially lower Kms for hydrolysis than do GTP and UTP. The Km for ATP hydrolysis is 15 microm for the 26S proteasome and 30 microm for the regulatory complex. Formation of the 26S proteasome from the RC and the 20S proteasome requires about 5 microm ATP. Although measurable degradation of Ubiquitin(Ub)-lysozyme conjugates occurs in the presence of CTP, GTP, and UTP, the best nucleotide for Ub-conjugate degradation by the 26S proteasome is ATP, with an estimated Km of 12 microm. In summary, our studies show that micromolar concentrations of ATP are sufficient for several 26S proteasome activities.
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PMID:Effects of nucleotides on assembly of the 26S proteasome and degradation of ubiquitin conjugates. 922 75

The titan mutants of Arabidopsis exhibit striking defects in seed development. The defining feature is the presence of abnormal endosperm with giant polyploid nuclei. Several TTN genes encode structural maintenance of chromosome proteins (condensins and cohesins) required for chromosome function at mitosis. Another TTN gene product (TTN5) is related to the ARL2 class of GTP-binding proteins. Here, we identify four additional TTN genes and present a general model for the titan phenotype. TTN1 was cloned after two tagged alleles were identified through a large-scale screen of T-DNA insertion lines. The predicted gene product is related to tubulin-folding cofactor D, which interacts with ARL2 in fission yeast (Schizosaccharomyces pombe) and humans to regulate tubulin dynamics. We propose that TTN5 and TTN1 function in a similar manner to regulate microtubule function in seed development. The titan phenotype can therefore result from disruption of chromosome dynamics (ttn3, ttn7, and ttn8) or microtubule function (ttn1 and ttn5). Three other genes have been identified that affect endosperm nuclear morphology. TTN4 and TTN9 appear to encode plant-specific proteins of unknown function. TTN6 is related to the isopeptidase T class of deubiquitinating enzymes that recycle polyubiquitin chains following protein degradation. Disruption of this gene may reduce the stability of the structural maintenance of chromosome complex. Further analysis of the TITAN network should help to elucidate the regulation of microtubule function and chromosome dynamics in seed development.
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PMID:Diversity of TITAN functions in Arabidopsis seed development. 1178 51

The mitochondrial ubiquitin ligase MITOL regulates mitochondrial dynamics. We report here that MITOL regulates mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) domain formation through mitofusin2 (Mfn2). MITOL interacts with and ubiquitinates mitochondrial Mfn2, but not ER-associated Mfn2. Mutation analysis identified a specific interaction between MITOL C-terminal domain and Mfn2 HR1 domain. MITOL mediated lysine-63-linked polyubiquitin chain addition to Mfn2, but not its proteasomal degradation. MITOL knockdown inhibited Mfn2 complex formation and caused Mfn2 mislocalization and MAM dysfunction. Sucrose-density gradient centrifugation and blue native PAGE retardation assay demonstrated that MITOL is required for GTP-dependent Mfn2 oligomerization. MITOL knockdown reduced Mfn2 GTP binding, resulting in reduced GTP hydrolysis. We identified K192 in the GTPase domain of Mfn2 as a major ubiquitination site for MITOL. A K192R mutation blocked oligomerization even in the presence of GTP. Taken together, these results suggested that MITOL regulates ER tethering to mitochondria by activating Mfn2 via K192 ubiquitination.
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PMID:MITOL regulates endoplasmic reticulum-mitochondria contacts via Mitofusin2. 2372 17

Mammalian cells encode three closely related Ras proteins, H-Ras, N-Ras, and K-Ras. Oncogenic K-Ras mutations frequently occur in human cancers, which lead to dysregulated cell proliferation and genomic instability. However, mechanistic role of the Ras isoform regulation have remained largely unknown. Furthermore, the dynamics and function of negative regulation of GTP-loaded K-Ras have not been fully investigated. Here, we demonstrate RasG, the Dictyostelium orthologue of K-Ras, is targeted for degradation by polyubiquitination. Both ubiquitination and degradation of RasG were strictly associated with RasG activity. High resolution tandem mass spectrometry (LC-MS/MS) analysis indicated that RasG ubiquitination occurs at C-terminal lysines equivalent to lysines found in human K-Ras but not in H-Ras and N-Ras homologues. Substitution of these lysine residues with arginines (4KR-RasG) diminished RasG ubiquitination and increased RasG protein stability. Cells expressing 4KR-RasG failed to undergo proper cytokinesis and resulted in multinucleated cells. Ectopically expressed human K-Ras undergoes polyubiquitin-mediated degradation in Dictyostelium, whereas human H-Ras and a Dictyostelium H-Ras homologue (RasC) are refractory to ubiquitination. Our results indicate the existence of GTP-loaded K-Ras orthologue-specific degradation system in Dictyostelium, and further identification of the responsible E3-ligase may provide a novel therapeutic approach against K-Ras-mutated cancers.
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PMID:Degradation of activated K-Ras orthologue via K-Ras-specific lysine residues is required for cytokinesis. 2433 82