2. Academic Validation
  3. HNK-1 sulfotransferase modulates α-dystroglycan glycosylation by 3-O-sulfation of glucuronic acid on matriglycan

HNK-1 sulfotransferase modulates α-dystroglycan glycosylation by 3-O-sulfation of glucuronic acid on matriglycan

  • Glycobiology. 2020 Sep 28;30(10):817-829. doi: 10.1093/glycob/cwaa024.
M Osman Sheikh 1,  David Venzke 2,  Mary E Anderson 2,  Takako Yoshida-Moriguchi 2,  John N Glushka 1,  Alison V Nairn 1,  Melina Galizzi 1,  Kelley W Moremen 1 3,  Kevin P Campbell 2,  Lance Wells 1 3
Affiliations

Affiliations

  • 1 Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.
  • 2 Department of Molecular Physiology and Biophysics, Department of Neurology, Howard Hughes Medical Institute, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.
  • 3 Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
PMID: 32149355 DOI: 10.1093/glycob/cwaa024
Abstract

Mutations in multiple genes required for proper O-mannosylation of α-dystroglycan are causal for congenital/limb-girdle muscular dystrophies and abnormal brain development in mammals. Previously, we and Others further elucidated the functional O-mannose glycan structure that is terminated by matriglycan, [(-GlcA-β3-Xyl-α3-)n]. This repeating disaccharide serves as a receptor for proteins in the extracellular matrix. Here, we demonstrate in vitro that HNK-1 sulfotransferase (HNK-1ST/carbohydrate sulfotransferase) sulfates terminal glucuronyl residues of matriglycan at the 3-hydroxyl and prevents further matriglycan polymerization by the LARGE1 Glycosyltransferase. While α-dystroglycan isolated from mouse heart and kidney is susceptible to exoglycosidase digestion of matriglycan, the functional, lower molecular weight α-dystroglycan detected in brain, where HNK-1ST expression is elevated, is resistant. Removal of the sulfate cap by a sulfatase facilitated dual-glycosidase digestion. Our data strongly support a tissue specific mechanism in which HNK-1ST regulates polymer length by competing with LARGE for the 3-position on the nonreducing GlcA of matriglycan.

Keywords

O-mannosylation; congenital muscular dystrophy; glycosylation; sulfotransferase; α-dystroglycan.

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