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POMK regulates dystroglycan function via LARGE-mediated elongation of matriglycan

By 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

Posted 07 Apr 2020
bioRxiv DOI: 10.1101/2020.04.06.007948 (published DOI: 10.7554/eLife.61388)

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. ### Competing Interest Statement The authors have declared no competing interest.

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