Journal article
POMK regulates dystroglycan function via LARGE1-mediated elongation of matriglycan
eLife, Vol.9, e61388
09/25/2020
DOI: 10.7554/eLife.61388
PMCID: PMC7556876
PMID: 32975514
Abstract
Matriglycan [-GlcA-β1,3-Xyl-α1,3-]
serves as a scaffold in many tissues for extracellular matrix proteins containing laminin-G domains including laminin, agrin, and perlecan. 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. Here, we show that Protein
-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). In the absence of
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. Solution NMR spectroscopy studies demonstrate that LARGE1 directly interacts with core M3 and binds preferentially to the phosphorylated form. Collectively, our study demonstrates that phosphorylation of core M3 by POMK enables LARGE1 to elongate matriglycan on α-DG, thereby preventing muscular dystrophy.
Details
- Title: Subtitle
- POMK regulates dystroglycan function via LARGE1-mediated elongation of matriglycan
- Creators
- Ameya S Walimbe - Howard Hughes Medical Institute, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, United StatesHidehiko Okuma - Howard Hughes Medical Institute, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, United StatesSoumya Joseph - Howard Hughes Medical Institute, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, United StatesTiandi Yang - Howard Hughes Medical Institute, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, United StatesTakahiro Yonekawa - Howard Hughes Medical Institute, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, United StatesJeffrey M Hord - Howard Hughes Medical Institute, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, United StatesDavid Venzke - Howard Hughes Medical Institute, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, United StatesMary E Anderson - Howard Hughes Medical Institute, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, United StatesSilvia Torelli - Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, United KingdomAdnan Manzur - Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, United KingdomMegan Devereaux - Howard Hughes Medical Institute, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, United StatesMarco Cuellar - Howard Hughes Medical Institute, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, United StatesSally Prouty - Howard Hughes Medical Institute, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, United StatesSaul Ocampo Landa - Howard Hughes Medical Institute, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, United StatesLiping Yu - Medical Nuclear Magnetic Resonance Facility, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, United StatesJunyu Xiao - 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, Beijing, ChinaJack E Dixon - Department of Pharmacology, Department of Cellular and Molecular Medicine, Department of Chemistry and Biochemistry, University of California, San Diego, San Diego, United StatesFrancesco Muntoni - National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, London, United KingdomKevin P Campbell - Howard Hughes Medical Institute, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, United States
- Resource Type
- Journal article
- Publication Details
- eLife, Vol.9, e61388
- DOI
- 10.7554/eLife.61388
- PMID
- 32975514
- PMCID
- PMC7556876
- NLM abbreviation
- Elife
- ISSN
- 2050-084X
- eISSN
- 2050-084X
- Publisher
- England
- Grant note
- Howard Hughes Medical Institute P50 NS053672 / NINDS NIH HHS T32 GM007337 / NIGMS NIH HHS 1 U54 NS053672 / Paul D. Wellstone Muscular Dystrophy Specialized Research Center grant
- Language
- English
- Date published
- 09/25/2020
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology; Medicine Administration
- Record Identifier
- 9984068385102771
Metrics
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