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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dystroglycans / chemistry
  • Dystroglycans / metabolism*
  • Glucuronic Acid / chemistry
  • Glucuronic Acid / metabolism*
  • Glycosylation
  • Mice
  • Sulfotransferases / chemistry
  • Sulfotransferases / isolation & purification
  • Sulfotransferases / metabolism*

Substances

  • Dystroglycans
  • Glucuronic Acid
  • HNK-1 sulfotransferase
  • Sulfotransferases