Disease relevance of Ubi-p63E

• A common feature of many human neurodegenerative diseases is the accumulation of insoluble ubiquitin-containing protein aggregates in the CNS [1].
• Parkin, an E3 ubiquitin ligase, has been found to be responsible for autosomal recessive juvenile parkinsonism characterized primarily by selective loss of dopaminergic neurons with subsequent defects in movements [2].
• In a recent issue of Nature, two independent reports by and show that loss of Drosophila PINK1 leads to defects in mitochondrial function resulting in male sterility, apoptotic muscle degeneration, and minor loss of dopamine neurons that is rescued by overexpression of the ubiquitin E3 ligase, parkin [3].
• IAPs contain N-terminal baculovirus IAP repeat domains and a C-terminal RING ubiquitin ligase domain [4].
• TRC8 encodes an E3-ubiquitin ligase disrupted in a family with hereditary renal cell carcinoma (RCC) [5].

Psychiatry related information on Ubi-p63E

• Ubiquitinated tau-positive inclusions have been reported in brains of Alzheimer's disease patients, but involvement of the ubiquitin-dependent proteasomal system in tau degradation remains controversial [6].

High impact information on Ubi-p63E

• Post-translational modification of proteins by the ubiquitin-like molecule SUMO (sumoylation) regulates their subcellular localization and affects their functional properties in vitro, but the physiological function of sumoylation in multicellular organisms is largely unknown [7].
• A critical mediator of cell-cycle transitions, the anaphase-promoting complex/cyclosome (APC/C), is an E3 ubiquitin ligase [8].
• Arthrin reacts with an anti-ubiquitin antibody, which demonstrates that its extra mass results from ubiquitin ligation [9].
• Approximately one in two nucleosomes of the transcribed copia and heat-shock 70 (hsp 70) genes in nonshocked cultured cells contains ubiquitin-H2A (uH2A) semihistone, a covalent conjugate of histone H2A and a small protein, ubiquitin [10].
• The Archipelago protein binds directly to Cyclin E and probably targets it for ubiquitin-mediated degradation [11].

Biological context of Ubi-p63E

• To investigate the pattern of expression of the polyubiquitin gene in developing animals, a polyubiquitin-lacZ fusion gene was introduced into the Drosophila genome by germ line transformation [12].
• Nedd4 is a HECT domain-containing E3 ubiquitin ligase that targets transmembrane receptors containing the PPSY motif for endocytosis [13].
• In the fruitfly Drosophila, as in all eukaryotes examined so far, some ubiquitin-coding sequences appear fused to unrelated open reading frames [14].
• Ubiquitin belongs to a multigene family [15].
• The 5' regulatory region of DUb80 shares common features with another ubiquitin fusion gene, DUb52, and with the ribosomal protein genes of Drosophila, Xenopus and mouse [14].

Anatomical context of Ubi-p63E

• For example, we discuss (i) advantages?disadvantages of cultured cells, (ii) types of expression vectors and "peptide tags" for recombinant protein production and surveillance, and (iii) standard approaches to determine whether a protein of interest is modified by ubiquitin and degraded by the proteasome [16].
• Here, we show that Neu is required at the plasma membrane for functional activity and that its RING finger domain acts as an E3 ubiquitin ligase [17].
• The tail protein is incorporated into the ribosome, and ubiquitin is thought to act as a chaperone [18].
• Here we show that ubiquitin-dependent mechanisms regulate synaptic development at the Drosophila neuromuscular junction (NMJ) [19].
• Although devoid of mutant protein, this neurodegeneration exhibits neuronal inclusion bodies that are Hsp70 and ubiquitin positive [20].

Associations of Ubi-p63E with chemical compounds

• DTX proteins have a basic N terminus; a central proline-rich region; and a C-terminal RING finger domain, a motif often found in ubiquitin-protein isopeptide ligases (E3) [21].
• Furthermore, AIP4-generated polyubiquitin chains are mainly conjugated through lysine 29 of ubiquitin in vivo, indicating a link between this type of chain and lysosomal degradation [22].
• Normal human ataxin-3--a polyubiquitin binding protein with ubiquitin protease activity--is a striking suppressor of polyglutamine neurodegeneration in vivo [23].
• The amino acid sequence (2547 residues) of the complete open reading frame of the X gene has 44% identity and 88% similarity to the Drosophila sequence and contains the conserved Cys and His domains characteristic of deubiquitinating enzymes, suggesting its biochemical function may be the hydrolysis of ubiquitin from protein-ubiquitin conjugates [24].
• Parkin is a ubiquitin-protein isopeptide ligase [25].

Physical interactions of Ubi-p63E

• We show that Commissureless binds to and is regulated by the ubiquitin ligase DNedd4 [26].
• UbcD4 can interact with the polyubiquitin-binding subunit of the proteasome [27].
• The ubiquitin-interacting motifs target the endocytic adaptor protein epsin for ubiquitination [28].

Regulatory relationships of Ubi-p63E

• Ubiquitin-activating/conjugating activity of TAFII250, a mediator of activation of gene expression in Drosophila [29].
• The cellular protein level of parkin is regulated by its ubiquitin-like domain [30].
• First, we tested the ability of a cDNA-based transgene encoding the adult muscle isoform of alpha-actinin under control of the heterologous ubiquitin promoter to rescue the lethality of null alpha-actinin mutations [31].

Other interactions of Ubi-p63E

• Regulation of Commissureless by the Ubiquitin Ligase DNedd4 Is Required for Neuromuscular Synaptogenesis in Drosophila melanogaster [32].
• Notch (N) signaling is an evolutionarily conserved mechanism that regulates many cell-fate decisions. deltex (dx) encodes an E3-ubiquitin ligase that binds to the intracellular domain of N and positively regulates N signaling [33].
• Deltex is a positive Notch signaling regulator that encodes a putative ubiquitin ligase of the ring finger type [13].
• We also characterize a mutation in mib1, a Drosophila homolog of mind bomb, another Delta-targeting ubiquitin ligase from zebrafish [34].
• Neuralized functions as an E3 ubiquitin ligase during Drosophila development [17].

Analytical, diagnostic and therapeutic context of Ubi-p63E

• Consistent with the reconstructions, peptide mapping places the ubiquitin linkage on lysine 118 in actin [35].
• Capillary electrophoresis assay for ubiquitin carboxyl-terminal hydrolases with chemically synthesized ubiquitin-valine as substrate [36].

References