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.
Highlights
The extracellular matrix (ECM) is essential for development, regeneration and physiological function in many tissues, and abnormalities in ECM structure can lead to disease (Rowe et al, 2008; Hudson et al, 2003)
Over eighteen genes are involved in the synthesis of the post translational modification terminating in matriglycan (Figure 1), and defects in this process cause dystroglycanopathies, congenital and limb-girdle muscular dystrophies that can be accompanied by brain and eye defects
To determine if matriglycan can be expressed in the absence of Protein O33 Mannose Kinase (POMK) function, and better understand the role of POMK in matriglycan synthesis, we studied skeletal muscle from a patient (NH13-284) with a POMK (D204N) mutation (Figure 2A) and congenital muscular dystrophy (CMD) accompanied by structural brain malformations
Summary
The extracellular matrix (ECM) is essential for development, regeneration and physiological function in many tissues, and abnormalities in ECM structure can lead to disease (Rowe et al, 2008; Hudson et al, 2003). The heteropolysaccharide [-GlcA-β1,3-Xyl-α1,3-]n (called matriglycan) is a scaffold for ECM proteins containing laminin-G (LG) domains (e.g. laminin, agrin, and perlecan) (Yoshida-Moriguchi et al, 2015; Hohenester, 2019; Michele et al, 2002; Ohtsubo et al, 2006) and has the remarkable capacity to be tuned during skeletal muscle development and regeneration (Goddeeris et al, 2013). Crystal structure studies have shown that a single glucuronic acidxylose disaccharide (GlcA-Xyl) repeat binds to laminin-α2 LG4 domain (Briggs et al, 2016; Hohenester et al, 1999), and there is a direct correlation between the number of GlcA-Xyl repeats on α-DG and its binding capacity for ECM ligands (Goddeeris et al, 2013; Inamori et al, 2012). Little is known about the mechanisms which control matriglycan elongation
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