LARGE1 processively polymerizes length-controlled matriglycan on prodystroglycan

Soumya Joseph, Nicholas J. Schnicker, Nicholas Spellmon, Zhen Xu, Rui Yan, Zhiheng Yu, Omar Davulcu, Tiandi Yang, Jesse Hopkins, Mary E. Anderson, David Venzke and Kevin P. Campbell ()
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Soumya Joseph: University of Iowa Roy J. and Lucille A. Carver College of Medicine
Nicholas J. Schnicker: University of Iowa Roy J. and Lucille A. Carver College of Medicine
Nicholas Spellmon: Howard Hughes Medical Institute
Zhen Xu: University of Iowa
Rui Yan: Howard Hughes Medical Institute
Zhiheng Yu: Howard Hughes Medical Institute
Omar Davulcu: Pacific Northwest National Laboratory, Environmental Molecular Sciences Laboratory
Tiandi Yang: University of Iowa Roy J. and Lucille A. Carver College of Medicine
Jesse Hopkins: Argonne National Laboratory
Mary E. Anderson: University of Iowa Roy J. and Lucille A. Carver College of Medicine
David Venzke: University of Iowa Roy J. and Lucille A. Carver College of Medicine
Kevin P. Campbell: University of Iowa Roy J. and Lucille A. Carver College of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Matriglycan is a linear glycan (xylose-β1,3-glucuronate)n, which binds proteins in the extracellular matrix that contain laminin-globular domains and Lassa Fever Virus. It is indispensable for neuromuscular function. Matriglycan of insufficient length can cause muscular dystrophy with abnormal brain and eye development. LARGE1 (Like-acetylglucosaminyltransferase-1) uniquely synthesizes matriglycan on dystroglycan. The mechanism of matriglycan synthesis is not obvious from cryo-EM reconstructions of LARGE1. However, by reconstituting activity in vitro on recombinant prodystroglycan we show that the presence of the dystroglycan N-terminal domain (DGN), phosphorylated core M3, and a xylose-glucuronate primer are necessary for matriglycan polymerization by LARGE1. By introducing active site mutations, we demonstrate that LARGE1 processively polymerizes matriglycan on prodystroglycan, with its length regulated by the dystroglycan prodomain, DGN. Our enzymatic analysis of LARGE1 uncovers the mechanism of matriglycan synthesis on dystroglycan, which can form the basis for therapeutic strategies to treat matriglycan-deficient neuromuscular disorders and arenaviral infections.

Date: 2025
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DOI: 10.1038/s41467-025-64080-z

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