The glucuronyltransferase B4GAT1 is required for initiation of LARGE-mediated α-dystroglycan functional glycosylation
| العنوان: | The glucuronyltransferase B4GAT1 is required for initiation of LARGE-mediated α-dystroglycan functional glycosylation |
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| المؤلفون: | Kevin P. Campbell, Greg Morgensen, Tobias Willer, Kei-ichiro Inamori, Liping Yu, Yuji Hara, Kevin M. Wright, Daniel Beltrán-Valero de Bernabé, David Venzke, Corinne Harvey |
| المصدر: | eLife, Vol 3 (2014) eLife |
| بيانات النشر: | eLife Sciences Publications Ltd, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Magnetic Resonance Spectroscopy, B4GAT1, Golgi Apparatus, Biochemistry, Substrate Specificity, Cell membrane, Mice, chemistry.chemical_compound, 0302 clinical medicine, Glucuronic Acid, Phosphorylation, Biology (General), Dystroglycans, 0303 health sciences, Xylose, biology, General Neuroscience, General Medicine, 3. Good health, Protein Transport, medicine.anatomical_structure, symbols, Medicine, Research Article, Subcellular Fractions, Glycan, Glycosylation, glycosylation, QH301-705.5, Protein subunit, Science, LARGE, N-Acetylglucosaminyltransferases, Models, Biological, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, symbols.namesake, alpha-dystroglycan, Glycosyltransferase, Dystroglycan, medicine, Animals, Humans, B3GNT1, Human Biology and Medicine, mouse, 030304 developmental biology, General Immunology and Microbiology, Fibroblasts, Golgi apparatus, Embryo, Mammalian, basement membrane, chemistry, Mutation, biology.protein, Mutant Proteins, 030217 neurology & neurosurgery, Function (biology) |
| الوصف: | Dystroglycan is a cell membrane receptor that organizes the basement membrane by binding ligands in the extracellular matrix. Proper glycosylation of the α-dystroglycan (α-DG) subunit is essential for these activities, and lack thereof results in neuromuscular disease. Currently, neither the glycan synthesis pathway nor the roles of many known or putative glycosyltransferases that are essential for this process are well understood. Here we show that FKRP, FKTN, TMEM5 and B4GAT1 (formerly known as B3GNT1) localize to the Golgi and contribute to the O-mannosyl post-phosphorylation modification of α-DG. Moreover, we assigned B4GAT1 a function as a xylose β1,4-glucuronyltransferase. Nuclear magnetic resonance studies confirmed that a glucuronic acid β1,4-xylose disaccharide synthesized by B4GAT1 acts as an acceptor primer that can be elongated by LARGE with the ligand-binding heteropolysaccharide. Our findings greatly broaden the understanding of α-DG glycosylation and provide mechanistic insight into why mutations in B4GAT1 disrupt dystroglycan function and cause disease. DOI: http://dx.doi.org/10.7554/eLife.03941.001 eLife digest Dystroglycan is a protein that is critical for the proper function of many tissues, especially muscles and brain. Dystroglycan helps to connect the structural network inside the cell with the matrix outside of the cell. The extracellular matrix fills the space between the cells to serve as a scaffold and hold cells together within a tissue. It is well established that the interaction of cells with their extracellular environments is important for structuring tissues, as well as for helping cells to specialize and migrate. These interactions also play a role in the progression of cancer. As is the case for many proteins, dystroglycan must be modified with particular sugar molecules in order to work correctly. Enzymes called glycosyltransferases are responsible for sequentially assembling a complex array of sugar molecules on dystroglycan. This modification is essential for making dystroglycan ‘sticky’, so it can bind to the components of the extracellular matrix. If sugar molecules are added incorrectly, dystroglycan loses its ability to bind to these components. This causes congenital muscular dystrophies, a group of diseases that are characterized by a progressive loss of muscle function. Willer et al. use a wide range of experimental techniques to investigate the types of sugar molecules added to dystroglycan, the overall structure of the resulting ‘sticky’ complex and the mechanism whereby it is built. This reveals that a glycosyltransferase known as B3GNT1 is one of the enzymes responsible for adding a sugar molecule to the complex. This enzyme was first described in the literature over a decade ago, and the name B3GNT1 was assigned, according to a code, to reflect the sugar molecule it was thought to transfer to proteins. However, Willer et al. (and independently, Praissman et al.) find that this enzyme actually attaches a different sugar modification to dystroglycan, and so should therefore be called B4GAT1 instead. Willer et al. find that the sugar molecule added by the B4GAT1 enzyme acts as a platform for the assembly of a much larger sugar polymer that cells use to anchor themselves within a tissue. Some viruses–including Lassa virus, which causes severe fever and bleeding–also use the ‘sticky’ sugar modification of dystroglycan to bind to and invade cells, causing disease in humans. Understanding the structure of this complex, and how these sugar modifications are added to dystroglycan, could therefore help to develop treatments for a wide range of diseases like progressive muscle weakening and viral infections. DOI: http://dx.doi.org/10.7554/eLife.03941.002 |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0284b0f6dbf5ee9757d2c74cd28b393e https://elifesciences.org/articles/03941 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....0284b0f6dbf5ee9757d2c74cd28b393e |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |