1. Biochemistry and Chemical Biology
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B4GAT1 is the priming enzyme for the LARGE-dependent functional glycosylation of α-dystroglycan

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Cite this article as: eLife 2014;3:e03943 doi: 10.7554/eLife.03943

Abstract

Recent studies demonstrated that mutations in B3GNT1, an enzyme proposed to be involved in poly-N-acetyllactosamine synthesis, were causal for congenital muscular dystrophy with hypoglycosylation of α-dystroglycan (secondary dystroglycanopathies). Since defects in the O-mannosylation protein glycosylation pathway are primarily responsible for dystroglycanopathies and with no established O-mannose initiated structures containing a β3 linked GlcNAc known, we biochemically interrogated this human enzyme. Here we report this enzyme is not a β-1,3-N-acetylglucosaminyltransferase with catalytic activity towards β-galactose but rather a β-1,4-glucuronyltransferase, designated B4GAT1, towards both α- and β-anomers of xylose. The dual-activity LARGE enzyme is capable of extending products of B4GAT1 and we provide experimental evidence that B4GAT1 is the priming enzyme for LARGE. Our results further define the functional O-mannosylated glycan structure and indicate that B4GAT1 is involved in the initiation of the LARGE-dependent repeating disaccharide that is necessary for extracellular matrix protein binding to O-mannosylated α-dystroglycan that is lacking in secondary dystroglycanopathies.

Article and author information

Author details

  1. Jeremy L Praissman

    University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. David H Live

    University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Shuo Wang

    University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Annapoorani Ramiah

    University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Zoeisha S Chinoy

    University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Geert-Jan Boons

    University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Kelley W Moremen

    University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Lance Wells

    University of Georgia, Athens, United States
    For correspondence
    lwells@ccrc.uga.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Suzanne R Pfeffer, Stanford University, United States

Publication history

  1. Received: July 9, 2014
  2. Accepted: October 1, 2014
  3. Accepted Manuscript published: October 3, 2014 (version 1)
  4. Version of Record published: November 11, 2014 (version 2)

Copyright

© 2014, Praissman et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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