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LARGE1 processively polymerizes length-controlled matriglycan on prodystroglycan

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  • Soumya Joseph

    (University of Iowa Roy J. and Lucille A. Carver College of Medicine
    University of Iowa Roy J. and Lucille A. Carver College of Medicine
    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
    University of Iowa)

  • 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
    University of Iowa Roy J. and Lucille A. Carver College of Medicine
    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
    University of Iowa Roy J. and Lucille A. Carver College of Medicine
    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
    University of Iowa Roy J. and Lucille A. Carver College of Medicine
    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
    University of Iowa Roy J. and Lucille A. Carver College of Medicine
    University of Iowa Roy J. and Lucille A. Carver College of Medicine)

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.

Suggested Citation

  • 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, 2025. "LARGE1 processively polymerizes length-controlled matriglycan on prodystroglycan," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64080-z
    DOI: 10.1038/s41467-025-64080-z
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    as
    1. M. Osman Sheikh & Chantelle J. Capicciotti & Lin Liu & Jeremy Praissman & Dahai Ding & Daniel G. Mead & Melinda A. Brindley & Tobias Willer & Kevin P. Campbell & Kelley W. Moremen & Lance Wells & Geer, 2022. "Cell surface glycan engineering reveals that matriglycan alone can recapitulate dystroglycan binding and function," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Michael Katz & Jonathan Weinstein & Maayan Eilon-Ashkenazy & Katrin Gehring & Hadas Cohen-Dvashi & Nadav Elad & Sarel J. Fleishman & Ron Diskin, 2022. "Structure and receptor recognition by the Lassa virus spike complex," Nature, Nature, vol. 603(7899), pages 174-179, March.
    3. Matthew M. Goddeeris & Biming Wu & David Venzke & Takako Yoshida-Moriguchi & Fumiaki Saito & Kiichiro Matsumura & Steven A. Moore & Kevin P. Campbell, 2013. "LARGE glycans on dystroglycan function as a tunable matrix scaffold to prevent dystrophy," Nature, Nature, vol. 503(7474), pages 136-140, November.
    4. Douglas Sammon & Anja Krueger & Marta Busse-Wicher & Rhodri Marc Morgan & Stuart M. Haslam & Benjamin Schumann & David C. Briggs & Erhard Hohenester, 2023. "Molecular mechanism of decision-making in glycosaminoglycan biosynthesis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Francisco Leisico & Juneina Omeiri & Christine Narvor & Joël Beaudouin & Michael Hons & Daphna Fenel & Guy Schoehn & Yohann Couté & David Bonnaffé & Rabia Sadir & Hugues Lortat-Jacob & Rebekka Wild, 2022. "Structure of the human heparan sulfate polymerase complex EXT1-EXT2," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
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