Work

N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy

Year: 2023

Type: article

Abstract: Dystroglycan (DG) requires extensive post-translational processing to function as a receptor for extracellular matrix proteins containing laminin-G-like (LG) domains. Matriglycan is an elongated polysaccharide of alternating xylose and glucuronic acid that is uniquely synthesized on α-dystroglycan (α-DG) by like-acetylglucosaminyltransferase-1 (LARGE1) and binds with high affinity to matrix proteins like laminin. Defects in the post-translational processing of α-DG that result in a shorter form of matriglycan reduce the size of α-DG and decrease laminin binding, leading to various forms of muscular dystrophy. However, little is known regarding mechanisms that generate full-length matriglycan on α-DG (~150-250 kDa). Here, we show that LARGE1 can only synthesize a short, non-elongated form of matriglycan in mouse skeletal muscle that lacks the DG N-terminus (α-DGN), resulting in a ~100-125 kDa α-DG. This smaller form of α-DG binds laminin and maintains specific force but does not prevent muscle pathophysiology, including reduced force induced by eccentric contractions and abnormalities in neuromuscular junctions. Collectively, our study demonstrates that α-DGN is required for LARGE1 to extend matriglycan to its full mature length on α-DG and thus prevent muscle pathophysiology.

Source: eLife

DOI: 10.7554/elife.82811