| First Author | Walimbe AS | Year | 2020 |
| Journal | Elife | Volume | 9 |
| PubMed ID | 32975514 | Mgi Jnum | J:302509 |
| Mgi Id | MGI:6508185 | Doi | 10.7554/eLife.61388 |
| Citation | Walimbe AS, et al. (2020) POMK regulates dystroglycan function via LARGE1-mediated elongation of matriglycan. Elife 9:e61388 |
| abstractText | Matriglycan [-GlcA-beta1,3-Xyl-alpha1,3-]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 alpha-dystroglycan (alpha-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-beta1,3-GlcNAc-beta1,4-Man) preceding matriglycan synthesis, is required for LARGE1-mediated generation of full-length matriglycan on alpha-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 alpha-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 alpha-DG, thereby preventing muscular dystrophy. |
