Prediction of structure and functional residues for <i>O</i>‐GlcNAcase, a divergent homologue of acetyltransferases

Schultz, Jörg; Pils, Birgit

doi:10.1016/s0014-5793(02)03322-7

Cited by 43 publications

(38 citation statements)

References 30 publications

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“…1), a 130-kDa enzyme that is highly concentrated in the cytosol but is also present in the nucleus of all cell types (Dong and Hart, 1994;Gao et al, 2001). The structure of O-GlcNAcase consists of an N-terminal glycosidase domain and a C-terminal region with homology to histone acetyltransferases (HATs) (Schultz and Pils, 2002;Toleman et al, 2004). Caspase-3 is known to cleave at a site between these two domains in vitro and upon apoptosis in vivo; however, the two halves of cleaved O-GlcNAcase remain physically associated and the glycosidase retains full activity (Butkinaree et al, 2008;Wells et al, 2002a).…”

Section: Introductionmentioning

confidence: 99%

The intersections betweenO-GlcNAcylation and phosphorylation: implications for multiple signaling pathways

Zeidan

Hart

2010

Journal of Cell Science

275

237

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SummaryA paradigm-changing discovery in biology came about when it was found that nuclear and cytosolic proteins could be dynamically glycosylated with a single O-linked b-N-acetylglucosamine (O-GlcNAc) moiety. O-GlcNAcylation is akin to phosphorylation: it occurs on serine and/or threonine side chains of proteins, and cycles rapidly upon cellular activation. O-GlcNAc and phosphate show a complex interplay: they can either competitively occupy a single site or proximal sites, or noncompetitively occupy different sites on a substrate. Phosphorylation regulates O-GlcNAc-cycling enzymes and, conversely, O-GlcNAcylation controls phosphate-cycling enzymes. Such crosstalk is evident in all compartments of the cell, a finding that is congruent with the fundamental role of O-GlcNAc in regulating nutrient-and stress-induced signal transduction. O-GlcNAc transferase is recruited to the plasma membrane in response to insulin and is targeted to substrates by forming transient holoenzyme complexes that have different specificities. Cytosolic O-GlcNAcylation is important for the proper transduction of signaling cascades such as the NFkB pathway, whereas nuclear O-GlcNAc is crucial for regulating the activity of numerous transcription factors. This Commentary focuses on recent findings supporting an emerging concept that continuous crosstalk between phosphorylation and O-GlcNAcylation is essential for the control of vital cellular processes and for understanding the mechanisms that underlie certain neuropathologies.

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Section: Introductionmentioning

confidence: 99%

The intersections betweenO-GlcNAcylation and phosphorylation: implications for multiple signaling pathways

Zeidan

Hart

2010

Journal of Cell Science

275

237

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“…The full-length OGA long form (OGA-L) has 916 amino acids transcribed from 16 exons (NM_012215) and a short isoform (OGA-S) contains 677 amino acids transcribed from first 10 exons (AF307332). Both isoforms are identical at the N-terminal hyaluronidase domain, but differ in that OGA-L has a histone acetyl transferase (HAT)-like domain at the C-terminus (Schultz and Pils, 2002;Toleman et al, 2004;Whisenhunt et al, 2006). The OGA-S isoform continues transcription through exon 10, skipping the splice junction and terminating with a unique 14 amino acid tail.…”

Section: Introductionmentioning

confidence: 99%

A lipid-droplet-targeted O-GlcNAcase isoform is a key regulator of the proteasome

Keembiyehetty

Krześlak

Love

et al. 2011

Journal of Cell Science

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Summary Protein-O-linked N-Acetyl-b-D-glucosaminidase (O-GlcNAcase, OGA; also known as hexosaminidase C) participates in a nutrientsensing, hexosamine signaling pathway by removing O-linked N-acetylglucosamine (O-GlcNAc) from key target proteins. Perturbations in O-GlcNAc signaling have been linked to Alzheimer's disease, diabetes and cancer. Mammalian O-GlcNAcase exists as two major spliced isoforms differing only by the presence (OGA-L) or absence (OGA-S) of a histone-acetyltransferase domain. Here we demonstrate that OGA-S accumulates on the surface of nascent lipid droplets with perilipin-2; both of these proteins are stabilized by proteasome inhibition. We show that selective downregulation of OGA-S results in global proteasome inhibition and the striking accumulation of ubiquitinylated proteins. OGA-S knockdown increased levels of perilipin-2 and perilipin-3 suggesting that O-GlcNAcdependent regulation of proteasomes might occur on the surface of lipid droplets. By locally activating proteasomes during maturation of the nascent lipid droplet, OGA-S could participate in an O-GlcNAc-dependent feedback loop regulating lipid droplet surface remodeling. Our findings therefore suggest a mechanistic link between hexosamine signaling and lipid droplet assembly and mobilization.

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“…An alternatively spliced transcript (MGEA5s), consisting of exons 1-10 and part of intron 10, encodes a 75-kDa protein that has nuclear localization (17). The COOH-terminal region of MGEA5, which is missing in the splice variant, is predicted to contain the O-GlcNAcase activity (3,18). We have previously reported linkage of type 2 diabetes and age at onset of diabetes to a region overlapping the MGEA5 locus on chromosome 10q in the San Antonio Family Diabetes Study (SAFADS) (19).…”

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confidence: 99%

A Single Nucleotide Polymorphism in MGEA5 Encoding O-GlcNAc–selective N-Acetyl-β-d Glucosaminidase Is Associated With Type 2 Diabetes in Mexican Americans

et al. 2005

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Prediction of structure and functional residues for O‐GlcNAcase, a divergent homologue of acetyltransferases

Cited by 43 publications

References 30 publications

The intersections betweenO-GlcNAcylation and phosphorylation: implications for multiple signaling pathways

The intersections betweenO-GlcNAcylation and phosphorylation: implications for multiple signaling pathways

A lipid-droplet-targeted O-GlcNAcase isoform is a key regulator of the proteasome

A Single Nucleotide Polymorphism in MGEA5 Encoding O-GlcNAc–selective N-Acetyl-β-d Glucosaminidase Is Associated With Type 2 Diabetes in Mexican Americans

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