Reversible defects in O-linked glycosylation and LDL receptor expression in a UDP-Gal/UDP-GalNAc 4-epimerase deficient mutant |
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| Authors: | D M Kingsley K F Kozarsky L Hobbie M Krieger |
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| Affiliation: | 1. Noncoding RNA Cancer Laboratory, Centre for Health Technologies, Faculty of Engineering and Information Technology, University of Technology, Sydney, NSW, Australia;2. The Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, Australia;1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA;2. Harvard Medical School, Boston, Massachusetts, USA;3. Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts, USA;4. Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, Texas, USA;5. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA;6. Penn Center for the Integration of Genetic Healthcare Technologies, University of Pennsylvania, Philadelphia, Pennsylvania, USA;7. Social and Behavioral Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA;8. Department of Medical Ethics and Health Policy, University of Pennsylvania, Philadelphia, Pennsylvania, USA;9. University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA;10. UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA;11. Department of Pharmacy, Pharmaceutical Outcomes Research and Policy Program, University of Washington, Seattle, Washington, USA |
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| Abstract: | We previously isolated an unusual hamster cell mutant (ldlD) that does not express LDL receptor activity unless it is cocultivated with other cells or grown in high concentrations of serum. We now show that ldlD cells are deficient in the enzyme UDP-galactose and UDP-N-acetylgalactosamine (GalNAc) 4-epimerase. When ldlD cells are grown in glucose-based media, they cannot synthesize enough UDP-galactose and UDP-GalNAc to allow normal synthesis of glycolipids and glycoproteins. The 4-epimerase deficiency accounts for all glycosylation defects previously observed in ldlD cells, including production of abnormal LDL receptors. All abnormal phenotypes of ldlD cells can be fully corrected by exogenous galactose and GalNAc. The separate effects of these sugars on LDL receptor activity suggest that O-linked carbohydrate chains are crucial for receptor stability. ldlD cells may be useful for structural and functional studies of many proteins, proteoglycans, and glycolipids containing galactose or GalNAc. |
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