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; Kevin P Campbell

doi:10.1038/s41467-025-64080-z

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LARGE1 processively polymerizes length-controlled matriglycan on prodystroglycan

Journal article

Open access

Peer reviewed

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, …

Nature communications, Vol.16(1), 9028

10/10/2025

DOI: 10.1038/s41467-025-64080-z

PMCID: PMC12514197

PMID: 41073435

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https://doi.org/10.1038/s41467-025-64080-zView

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Abstract

Matriglycan is a linear glycan (xylose-β1,3-glucuronate) , 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.

Animals

Catalytic Domain

Cryoelectron Microscopy

Dystroglycans - chemistry

Dystroglycans - metabolism

Humans

N-Acetylglucosaminyltransferases - chemistry

N-Acetylglucosaminyltransferases - genetics

N-Acetylglucosaminyltransferases - metabolism

Polymerization

Polysaccharides - metabolism

Details

Title: Subtitle: LARGE1 processively polymerizes length-controlled matriglycan on prodystroglycan
Creators: Soumya Joseph - University of Iowa
Nicholas J Schnicker - University of Iowa
Nicholas Spellmon - Janelia Research Campus
Zhen Xu - University of Iowa
Rui Yan - Janelia Research Campus
Zhiheng Yu - Janelia Research Campus
Omar Davulcu - Environmental Molecular Sciences Laboratory
Tiandi Yang - University of Iowa
Jesse Hopkins - Argonne National Laboratory
Mary E Anderson - University of Iowa
David Venzke - University of Iowa
Kevin P Campbell - University of Iowa
Resource Type: Journal article
Publication Details: Nature communications, Vol.16(1), 9028
DOI: 10.1038/s41467-025-64080-z
PMID: 41073435
PMCID: PMC12514197
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: NATURE PORTFOLIO
Grant note: P30 GM138395 / NIGMS NIH HHS P41 GM103622 / NIGMS NIH HHS U54 NS053672 / NINDS NIH HHS U24 GM129547 / NIGMS NIH HHS P50 NS053672 / NINDS NIH HHS S10 OD018090 / NIH HHS
Language: English
Date published: 10/10/2025
Academic Unit: Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Medicine Administration
Record Identifier: 9985014876102771

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