LARGE1 processively polymerizes length-controlled matriglycan on prodystroglycan
Matriglycan is a linear glycan (xylose-β1,3-glucuronate)<sub>n</sub>, 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.
Authors
- Mary E. Anderson (ORCID: https://orcid.org/0000-0001-5342-530X)
- David Venzke (ORCID: https://orcid.org/0000-0001-8180-9562)
- Jesse B. Hopkins (ORCID: https://orcid.org/0000-0001-8554-8072)
- Soumya Joseph (ORCID: https://orcid.org/0000-0002-0487-1378)
- Nicholas Schnicker (ORCID: https://orcid.org/0000-0002-5189-4943)
- Rui Yan (ORCID: https://orcid.org/0000-0002-0167-2816)
- Zhiheng Yu (ORCID: https://orcid.org/0000-0002-7114-2570)
- Nicholas Spellmon (ORCID: https://orcid.org/0000-0002-2045-1373)
- Tiandi Yang (ORCID: https://orcid.org/0000-0002-6634-0847)
- Kevin P. Campbell (ORCID: https://orcid.org/0000-0003-2066-5889)
- Omar Davulcu (ORCID: https://orcid.org/0000-0002-7056-6435)
- Zhen Xu (ORCID: https://orcid.org/0000-0001-8855-0565)
Institutions
- University of Iowa (US)
- Argonne National Laboratory (US)
- Howard Hughes Medical Institute (US)
- Pacific Northwest National Laboratory (US)
- Janelia Research Campus (US)
- Environmental Molecular Sciences Laboratory (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-10
- DOI
- https://doi.org/10.1038/s41467-025-64080-z
- Citations
- 1
- Primary Topic
- Virus-based gene therapy research
- Type
- article
- Field-Weighted Citation Impact
- 1.82
Funders
- U.S. Department of Energy
- Oregon Health and Science University
- National Institutes of Health
- Office of Science
- Roy J. and Lucille A. Carver College of Medicine, University of Iowa
- National Institute of General Medical Sciences
- Biological and Environmental Research
- Argonne National Laboratory