ArticleThe Journal of biological chemistry2015
Impaired O-linked N-acetylglucosaminylation in the endoplasmic reticulum by mutated epidermal growth factor (EGF) domain-specific O-linked N-acetylglucosamine transferase found in Adams-Oliver syndrome.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 37 citations in OpenAlex.
- Crystal structure of epidermal growth factor domain-specificPNAS nexus · 2026Article
- Significant Roles of NotchMolecules (Basel, Switzerland) · 2022Review
- Regulation of myeloid and lymphoid cell development by O-glycans on Notch.Frontiers in molecular biosciences · 2022Review
- Current Views on the Roles ofBiomolecules · 2021Review
- Other Types of Glycosylation.Advances in experimental medicine and biology · 2021Article
- A Chemoenzymatic Method Based on Easily Accessible Enzymes for Profiling Protein O-GlcNAcylation.Analytical chemistry · 2020Article
- Article
- Pleiotropic Role of Notch Signaling in Human Skin Diseases.International journal of molecular sciences · 2020Review
- Disrupted glycosylation of lipids and proteins is a cause of neurodegeneration.Brain : a journal of neurology · 2020Review
- Decoding the PTM-switchboard of Notch.Biochimica et biophysica acta. Molecular cell research · 2019Review
- Multiple roles for O-glycans in Notch signalling.FEBS letters · 2018Review
- Structural Divergence inMolecules (Basel, Switzerland) · 2018Article
- EOGT andBiochemical Society transactions · 2017Review
- O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals.eLife · 2017Article
- Mapping Sites of O-Glycosylation and Fringe Elongation on Drosophila Notch.The Journal of biological chemistry · 2016Article
- Glycosylation and other PTMs alterations in neurodegenerative diseases: Current status and future role in neurotrauma.Electrophoresis · 2016Review
- Notch Signaling and the Skeleton.Endocrine reviews · 2016Review
- The multiple roles of epidermal growth factor repeat O-glycans in animal development.Glycobiology · 2015Review
- Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome.American journal of human genetics · 2015Article
- A mutant O-GlcNAcase as a probe to reveal global dynamics of protein O-GlcNAcylation during Drosophila embryonic development.The Biochemical journal · 2015Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Epidermal growth factor (EGF) domain-specific O-linked N-acetylglucosamine (EOGT) is an endoplasmic reticulum (ER)-resident O-linked N-acetylglucosamine (O-GlcNAc) transferase that acts on EGF domain-containing proteins such as Notch receptors. Recently, mutations in EOGT have been reported in patients with Adams-Oliver syndrome (AOS). Here, we have characterized enzymatic properties of mouse EOGT and EOGT mutants associated with AOS. Simultaneous expression of EOGT with Notch1 EGF repeats in human embryonic kidney 293T (HEK293T) cells led to immunoreactivity with the CTD110.6 antibody in the ER. Consistent with the GlcNAc modification in the ER, the enzymatic properties of EOGT are distinct from those of Golgi-resident GlcNAc transferases; the pH optimum of EOGT ranges from 7.0 to 7.5, and the Km value for UDP N-acetylglucosamine (UDP-GlcNAc) is 25 μm. Despite the relatively low Km value for UDP-GlcNAc, EOGT-catalyzed GlcNAcylation depends on the hexosamine pathway, as revealed by the increased O-GlcNAcylation of Notch1 EGF repeats upon supplementation with hexosamine, suggesting differential regulation of the luminal UDP-GlcNAc concentration in the ER and Golgi. As compared with wild-type EOGT, O-GlcNAcylation in the ER is nearly abolished in HEK293T cells exogenously expressing EOGT variants associated with AOS. Introduction of the W207S mutation resulted in degradation of the protein via the ubiquitin-proteasome pathway, although the stability and ER localization of EOGT(R377Q) were not affected. Importantly, the interaction between UDP-GlcNAc and EOGT(R377Q) was impaired without adversely affecting the acceptor substrate interaction. These results suggest that impaired glycosyltransferase activity in mutant EOGT proteins and the consequent defective O-GlcNAcylation in the ER constitute the molecular basis for AOS.
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