{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n LARGE1 is a bifunctional glycosyltransferase that catalyzes the final steps in the post‐translational modification of α‑dystroglycan (α‑DG). In this role, LARGE1 transfers xylose and glucuronic acid from their UDP‐activated donors to form a repeating disaccharide polymer (matriglycan) on a primed O‑mannosyl glycan of α‑DG, which is essential for high‐affinity binding to extracellular matrix ligands such as laminin."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " LARGE1’s activity is dependent on prior steps of O‑mannosyl glycosylation (for example, mediated by POMT2) and, in so doing, it effectively endows α‑DG with its receptor function that is critical for basement membrane assembly and cell–matrix interactions."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Disruption of LARGE1 function via mutations or misregulation results in underglycosylation of α‑DG, which is implicated in a spectrum of dystroglycanopathies characterized by muscular dystrophy and central nervous system abnormalities."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In addition, studies in malignant contexts have revealed that LARGE1 expression levels correlate with tumor cell behavior; for instance, downregulation of LARGE1 is associated with loss of matriglycan and impaired laminin binding in rhabdomyosarcoma, while upregulation in liver cancer cells appears to promote cell proliferation, migration, and invasion, and copy number alterations involving LARGE1 have been observed in glioblastoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, the extent of matriglycan polymerization by LARGE1 can be modulated by competing enzymes such as HNK‑1 sulfotransferase, which caps the terminal glucuronic acid residue, thereby regulating polymer length in a tissue‐specific manner."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Collectively, these findings underscore the central role of LARGE1 in both maintaining normal tissue integrity through proper α‑DG glycosylation and contributing to disease pathogenesis when its function is compromised or aberrantly regulated.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Tobias Willer, Kei-Ichiro Inamori, David Venzke, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The glucuronyltransferase B4GAT1 is required for initiation of LARGE-mediated α-dystroglycan functional glycosylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.03941"}], "href": "https://doi.org/10.7554/eLife.03941"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25279699"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25279699"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Peng Zhang, Huaiyu Hu "}, {"type": "b", "children": [{"type": "t", "text": "Differential glycosylation of α-dystroglycan and proteins other than α-dystroglycan by like-glycosyltransferase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Glycobiology (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/glycob/cwr131"}], "href": "https://doi.org/10.1093/glycob/cwr131"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21930648"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21930648"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Kei-Ichiro Inamori, Aaron M Beedle, Daniel Beltrán-Valero de Bernabé, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LARGE2-dependent glycosylation confers laminin-binding ability on proteoglycans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Glycobiology (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/glycob/cww075"}], "href": "https://doi.org/10.1093/glycob/cww075"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27496765"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27496765"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Benedetta Righino, Manuela Bozzi, Davide Pirolli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification and Modeling of a GT-A Fold in the α-Dystroglycan Glycosylating Enzyme LARGE1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Chem Inf Model (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/acs.jcim.0c00281"}], "href": "https://doi.org/10.1021/acs.jcim.0c00281"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32356985"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32356985"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Daniel Beltrán, Mary E Anderson, Narendra Bharathy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Exogenous expression of the glycosyltransferase LARGE1 restores α-dystroglycan matriglycan and laminin binding in rhabdomyosarcoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Skelet Muscle (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13395-019-0195-0"}], "href": "https://doi.org/10.1186/s13395-019-0195-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31054580"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31054580"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Min Wang, Haiyan Tao, Ping Huang "}, {"type": "b", "children": [{"type": "t", "text": "Clinical significance of LARGE1 in progression of liver cancer and the underlying mechanism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2021.145493"}], "href": "https://doi.org/10.1016/j.gene.2021.145493"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33588034"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33588034"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Lisandra Muñoz-Hidalgo, Teresa San-Miguel, Javier Megías, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Somatic copy number alterations are associated with EGFR amplification and shortened survival in patients with primary glioblastoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neoplasia (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neo.2019.09.001"}], "href": "https://doi.org/10.1016/j.neo.2019.09.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31751860"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31751860"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "M Osman Sheikh, David Venzke, Mary E Anderson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HNK-1 sulfotransferase modulates α-dystroglycan glycosylation by 3-O-sulfation of glucuronic acid on matriglycan."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Glycobiology (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/glycob/cwaa024"}], "href": "https://doi.org/10.1093/glycob/cwaa024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32149355"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32149355"}]}]}]}