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bioRxiv · 10.1101/2022.08.09.502851

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

Okuma, H.·Hord, J. M.·Chandel, I.·Anderson, M. E.·Venzke, D.·Walimbe, A. S.·Joseph, S.·Gastel, Z.·Hara, Y.·Saito, F.·Matsumura, K.·Campbell, K. P.
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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 -dystroglycan (-DG) by like-acetylglucosaminyltransferase-1 (LARGE1) and binds with high affinity to matrix proteins like laminin. Defects in the post-translational processing of -DG that result in a shorter form of matriglycan reduce the size of -DG and decrease laminin binding, leading to various forms of muscular dystrophy. However, little is known regarding mechanisms that generate full-length matriglycan on -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 (-DGN), resulting in a ~100-125 kDa -DG. This smaller form of -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 -DGN is required for LARGE1 to extend matriglycan to its full mature length on -DG and thus prevent muscle pathophysiology.

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Okuma, H., Hord, J. M., Chandel, I., Anderson, M. E., Venzke, D., Walimbe, A. S., Joseph, S., Gastel, Z., Hara, Y., Saito, F., Matsumura, K., Campbell, K. P.. 2022-08-09. Dystroglycan N-terminal domain enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy. https://doi.org/10.1101/2022.08.09.502851

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