B4GAT1 is the priming enzyme for the LARGE-dependent functional glycosylation of α-dystroglycan
| العنوان: | B4GAT1 is the priming enzyme for the LARGE-dependent functional glycosylation of α-dystroglycan |
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| المؤلفون: | Geert-Jan Boons, Zoeisha S. Chinoy, Kelley W. Moremen, Jeremy L. Praissman, Shuo Wang, Lance Wells, David Live, Annapoorani Ramiah |
| المصدر: | eLife eLife, Vol 3 (2014) |
| بيانات النشر: | eLife Sciences Publications, Ltd, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Glycosylation, B4GAT1, Disaccharide, Disaccharides, Biochemistry, Substrate Specificity, chemistry.chemical_compound, Biology (General), Dystroglycans, Peptide sequence, chemistry.chemical_classification, congenital muscular dystrophy, 0303 health sciences, Xylose, biology, General Neuroscience, 030302 biochemistry & molecular biology, Stereoisomerism, General Medicine, Medicine, Extracellular matrix protein binding, Research Article, Glycan, QH301-705.5, Science, Molecular Sequence Data, N-Acetylglucosaminyltransferases, Models, Biological, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, alpha-dystroglycan, Humans, B3GNT1, Amino Acid Sequence, Pentosyltransferases, human, Human Biology and Medicine, 030304 developmental biology, General Immunology and Microbiology, HEK 293 cells, O-mannosylation, carbohydrates (lipids), Kinetics, HEK293 Cells, Enzyme, Solubility, chemistry, Biocatalysis, Uridine Diphosphate Glucuronic Acid, biology.protein, Trisaccharides |
| الوصف: | Recent studies demonstrated that mutations in B3GNT1, an enzyme proposed to be involved in poly-N-acetyllactosamine synthesis, were causal for congenital muscular dystrophy with hypoglycosylation of α-dystroglycan (secondary dystroglycanopathies). Since defects in the O-mannosylation protein glycosylation pathway are primarily responsible for dystroglycanopathies and with no established O-mannose initiated structures containing a β3 linked GlcNAc known, we biochemically interrogated this human enzyme. Here we report this enzyme is not a β-1,3-N-acetylglucosaminyltransferase with catalytic activity towards β-galactose but rather a β-1,4-glucuronyltransferase, designated B4GAT1, towards both α- and β-anomers of xylose. The dual-activity LARGE enzyme is capable of extending products of B4GAT1 and we provide experimental evidence that B4GAT1 is the priming enzyme for LARGE. Our results further define the functional O-mannosylated glycan structure and indicate that B4GAT1 is involved in the initiation of the LARGE-dependent repeating disaccharide that is necessary for extracellular matrix protein binding to O-mannosylated α-dystroglycan that is lacking in secondary dystroglycanopathies. DOI: http://dx.doi.org/10.7554/eLife.03943.001 eLife digest Dystroglycan is a protein that is essential for muscles to function correctly, and helps to connect the interior framework of muscle cells with the external matrix of molecules that hold the cells together in the tissue. As is the case for many proteins, dystroglycan must have particular carbohydrate molecules joined to it in order to work correctly. Enzymes called glycosyltransferases assist with the reactions that build the carbohydrates on a protein. Mutations in multiple glycosyltransferases that add carbohydrates to dystroglycan can cause a group of diseases that are characterized by a progressive loss of muscle function, known as congenital muscular dystrophies. Praissman et al. use biochemical experimentation to investigate the role of one of these enzymes, known as B3GNT1. The enzyme's name is based on a code that describes which carbohydrate it helps to bind to proteins. However, Praissman et al. (and independently, Willer et al.) discovered that this enzyme actually works with a different donor and acceptor than previously thought, and so should be called B4GAT1 instead. Praissman et al. propose that the B4GAT1 enzyme starts the process of forming the carbohydrate structures that help muscle cells bind to the muscle tissue matrix. B4GAT1 forms short carbohydrates on the surface of the part of dystroglycan that sits on the surface of cells. These carbohydrates are then extended into longer chains by another glycosyltransferase called LARGE. The results of Praissman et al. suggest that another enzyme is also involved in this process, which will require further studies to identify. Understanding the role of B4GAT1 and other glycosyltransferases that build functionally glycosylated dystroglycan could help to develop treatments for diseases such as muscular dystrophies. DOI: http://dx.doi.org/10.7554/eLife.03943.002 |
| تدمد: | 2050-084X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::66e7b5e1e6cd59832c00bfdfdd441441 https://doi.org/10.7554/elife.03943 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....66e7b5e1e6cd59832c00bfdfdd441441 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2050084X |
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