matriglycan

Matriglycan is a distinctive glycan modification on the extracellular matrix receptor alpha-dystroglycan (α-DG). It is essential for the dystrophin-glycoprotein complex to anchor the cytoskeleton to the extracellular matrix by enabling binding to laminin and other matrix proteins. Matriglycan was identified as the laminin-binding determinant of α-DG and is required for proper muscle, brain, and eye development.

Structure and biosynthesis: Matriglycan consists of a repeating disaccharide unit, Xyl-α1,3-GlcA-β1,3, linked head-to-tail to a serine residue on α-DG within its mucin-like domain. The polymer grows by successive addition of Xyl and GlcA units, yielding a long, negatively charged chain that presents laminin G domain binding sites. Its extension depends on the coordinated activity of specific glycosyltransferases, notably the LARGE enzyme, which has both xylosyltransferase and glucuronyltransferase activities. Other enzymes in the dystroglycan glycosylation pathway, including POMT1/2, POMGNT1, FKTN and FKRP, contribute to the initial protein O-mannosyl glycan scaffold that matriglycan builds upon.

Function: The presence and length of matriglycan determine the affinity of α-DG for extracellular matrix ligands such as laminin, agrin, and perlecan; longer matriglycan chains generally correlate with stronger laminin binding.

Clinical significance: Defects in matriglycan synthesis or elongation cause dystroglycanopathies, a spectrum of muscular dystrophies and brain malformations. Conditions include congenital muscular dystrophy with brain involvement and certain limb-girdle muscular dystrophies; severities vary with the degree of laminin-binding deficiency. Research aims to restore matriglycan formation by modulating LARGE or related enzymes.