2. Academic Validation
  3. POMK regulates dystroglycan function via LARGE1-mediated elongation of matriglycan

POMK regulates dystroglycan function via LARGE1-mediated elongation of matriglycan

  • Elife. 2020 Sep 25;9:e61388. doi: 10.7554/eLife.61388.
Ameya S Walimbe 1,  Hidehiko Okuma 1,  Soumya Joseph 1,  Tiandi Yang 1,  Takahiro Yonekawa 1,  Jeffrey M Hord 1,  David Venzke 1,  Mary E Anderson 1,  Silvia Torelli 2,  Adnan Manzur 2,  Megan Devereaux 1,  Marco Cuellar 1,  Sally Prouty 1,  Saul Ocampo Landa 1,  Liping Yu 3,  Junyu Xiao 4,  Jack E Dixon 5,  Francesco Muntoni 2 6,  Kevin P Campbell 1
Affiliations

Affiliations

  • 1 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.
  • 2 Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, United Kingdom.
  • 3 Medical Nuclear Magnetic Resonance Facility, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, United States.
  • 4 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, China.
  • 5 Department of Pharmacology, Department of Cellular and Molecular Medicine, Department of Chemistry and Biochemistry, University of California, San Diego, San Diego, United States.
  • 6 National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
PMID: 32975514 DOI: 10.7554/eLife.61388
Abstract

Matriglycan [-GlcA-β1,3-Xyl-α1,3-]n 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 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). 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. 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.

Keywords

LARGE; POMK; biochemistry; chemical biology; dystroglycan; laminin; matriglycan; mouse; muscular dystrophy.

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