Flowjo 7.6.5 free download1/17/2023 ![]() ![]() Like-acetyl-glucosaminyltransferase 1 (LARGE1) synthesizes matriglycan on the cell-surface glycoprotein, α-dystroglycan (α-DG) ( Inamori et al., 2012). congenital and limb-girdle muscular dystrophies that can be accompanied by brain and eye defects. Over 18 genes are involved in the synthesis of the post-translational modification terminating in matriglycan ( Figure 1), and defects in this process cause dystroglycanopathies, i.e. laminin, agrin, and perlecan) ( Yoshida-Moriguchi and Campbell, 2015 Hohenester, 2019 Michele et al., 2002 Ohtsubo and Marth, 2006) and has the remarkable capacity to be tuned during skeletal muscle development and regeneration ( Goddeeris et al., 2013). The heteropolysaccharide n (called matriglycan) is a scaffold for ECM proteins containing laminin-G (LG) domains (e.g. The extracellular matrix (ECM) is essential for development, regeneration and physiological function in many tissues, and abnormalities in ECM structure can lead to disease ( Rowe and Weiss, 2008 Hudson et al., 2003). Collectively, our study demonstrates that phosphorylation of core M3 by POMK enables LARGE1 to elongate matriglycan on α-DG, thereby preventing muscular dystrophy. Solution NMR spectroscopy studies demonstrate that LARGE1 directly interacts with core M3 and binds preferentially to the phosphorylated form. In the absence of Pomk gene expression in mouse skeletal muscle, LARGE1 synthesizes a very short matriglycan resulting in a ~ 90 kDa α-DG which binds laminin but cannot prevent eccentric contraction-induced force loss or muscle pathology. Here, we show that Protein O-Mannose Kinase (POMK), which phosphorylates mannose of core M3 (GalNAc-β1,3-GlcNAc-β1,4-Man) preceding matriglycan synthesis, is required for LARGE1-mediated generation of full-length matriglycan on α-DG (~150 kDa). Like-acetyl-glucosaminyltransferase 1 (LARGE1) synthesizes and extends matriglycan on α-dystroglycan (α-DG) during skeletal muscle differentiation and regeneration however, the mechanisms which regulate matriglycan elongation are unknown. Matriglycan n serves as a scaffold in many tissues for extracellular matrix proteins containing laminin-G domains including laminin, agrin, and perlecan. National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, United Kingdom.Department of Pharmacology, Department of Cellular and Molecular Medicine, Department of Chemistry and Biochemistry, University of California, San Diego, United States.The State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking-Tsinghua Center for Life Sciences, Peking University, China.Carver College of Medicine, United States Medical Nuclear Magnetic Resonance Facility, University of Iowa Roy J.Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, United Kingdom.Carver College of Medicine, The University of Iowa, United States ![]() Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. ![]() Howard Hughes Medical Institute, Senator Paul D. ![]()
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