Modification by O-GlcNAc involves a growing number of eucaryotic nuclear and cytosolic proteins. Glycosylation of intracellular proteins is a dynamic process that in several cases competes with and acts as a reciprocal modification system to phosphorylation. O-Linked -N-acetylglucosamine transferase (OGT) levels are highest in the brain, and neurodegenerative disorders such as Alzheimer disease have been shown to involve abnormally phosphorylated key proteins, probably as a result of hypoglycosylation. Here, we show that the neurodegenerative disease protein ataxin-10 (Atx-10) is associated with cytoplasmic OGT p110 in the brain. In PC12 cells and pancreas, this association is competed by the shorter OGT p78 splice form, which is down-regulated in brain. Overexpression of Atx-10 in PC12 cells resulted in the reconstitution of the Atx-10-OGT p110 complex and enhanced intracellular glycosylation activity. Moreover, in an in vitro enzyme assay using PC12 cell extracts, Atx-10 increased OGT activity 2-fold. These data indicate that Atx-10 might be essential for the maintenance of a critical intracellular glycosylation level and homeostasis in the brain.Since its discovery (1), the modification of intracellular proteins by a single GlcNAc moiety has emerged as a major signaling event involving a growing number of proteins (2, 3). Changes in O-GlcNAc glycosylation levels were shown to have a regulatory effect on diverse cellular processes such as proteasome activity (4), transcription (5), and enzyme function (6). The enzyme OGT 2 is encoded by a single gene, which is highly conserved among metazoans (7). Several splice forms have been described that vary in the length of the protein N terminus and subcellular localization (8). Full-length OGT is a 110-kDa polypeptide consisting of two domains. The N-terminal half contains multiple tetratricopeptide repeats (TPR) that adopt a bent superhelical fold related to the armadillo repeat motif (9). The C-terminal portion shows glycosyltransferase activity, whereas the TPR domain is responsible for substrate binding and OGT oligomerization (9 -11). Originally, the enzyme was isolated from rat liver cytosol as an apparent heterotrimer consisting of two p110 subunits and one p78 subunit (12). The p110 subunit, which exerts full catalytic activity by itself, is ubiquitously expressed, whereas the p78 splice variant that lacks most of the TPR repeats appears to be restricted to certain tissues such as liver, kidney, and muscle (13).Dysregulated OGT activity leading to hyper-or hypoglycosylation of target proteins is believed to be involved in the pathogenesis of disorders such as type II diabetes (6, 14) and Alzheimer disease (15). Protein glycosylation with GlcNAc may directly compete for serine and threonine residues with phosphorylation, thus creating a sensitive balance between positive and negative regulatory signals (16). Perturbations of this reciprocal relationship might lead to cell degeneration as in the case of hyperphosphorylated tau (17,18). It has become evident fro...
The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article.
The interaction of neurotrophins and their tyrosine kinase receptors (trks) is essential for differentiation and survival of brain cells. In Alzheimer's disease (AD), the number of neurotrophins and receptors is markedly decreased. The cause of this reduction is unclear, but the role of beta-amyloid (Abeta) seems central in understanding the mechanisms controlling neurotrophin and trk expression. In the study reported here, we exposed SHSY5Y neuroblastoma cells to Abeta or hydrogen peroxide (H(2)O(2)) and measured the expression of trk-A and p75 at the protein and molecular levels. Both Abeta and H(2)O(2) induced oxidative stress (measured by a decrease in cellular glutathione), which decreased trk-A levels and increased p75 levels, decreased messenger RNA (mRNA) levels of both receptors, and increased nerve growth factor (NGF) secretion. Pretreatment of cells with the antioxidant melatonin returned levels of protein expression, mRNA, and NGF secretion to normal. These results are significant, as they can help in the planning and implementation of AD treatment strategies involving neurotrophins.
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