POMK regulates dystroglycan function via LARGE1-mediated elongation of matriglycan
Year: 2020
Type: article
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-acetylglucosaminyltransferase-1 (LARGE) 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 LARGE-mediated generation of full-length matriglycan on α-DG (∼150 kDa). In the absence of POMK , LARGE synthesizes a very short matriglycan resulting in a ∼90 kDa α-DG in mouse skeletal muscle which binds laminin but cannot prevent eccentric contraction-induced force loss or muscle pathology. Solution NMR spectroscopy studies demonstrate that LARGE directly interacts with core M3 and binds preferentially to the phosphorylated form. Collectively, our study demonstrates that phosphorylation of core M3 by POMK enables LARGE to elongate matriglycan on α-DG, thereby preventing muscular dystrophy.
Source: eLife
DOI: 10.7554/elife.61388
Authors: Ameya S. Walimbe, Hidehiko Okuma, Soumya Joseph, Tiandi Yang, Takahiro Yonekawa, Jeffrey M. Hord, David Venzke, Mary E. Anderson, Silvia Torelli, Adnan Manzur, Megan Devereaux, Marco Cuellar, Sally Prouty, Saul Ocampo Landa, Liping Yu, Junyu Xiao, Jack E. Dixon, Francesco Muntoni, Kevin P. Campbell
Institutions: University of Iowa, Howard Hughes Medical Institute, Great Ormond Street Hospital, University College London, Peking University, Center for Life Sciences, State Key Laboratory of Protein and Plant Gene Research, University of California San Diego, National Institute for Health and Care Research, UCL Biomedical Research Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: Howard Hughes Medical Institute, NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, National Institute for Health and Care Research, University College London, Great Ormond Street Hospital for Children, Medical Research Council, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
OpenAlex ID: W3087924098