Matriglycan: a novel polysaccharide that links dystroglycan to the basement membrane

Abstract

Associations between cells and the basement membrane are critical for a variety of biological events including cell proliferation, cell migration, cell differentiation and the maintenance of tissue integrity. Dystroglycan is a highly glycosylated basement membrane receptor, and is involved in physiological processes that maintain integrity of the skeletal muscle, as well as development and function of the central nervous system. Aberrant O-glycosylation of the α subunit of this protein, and a concomitant loss of dystroglycan's ability to function as a receptor for extracellular matrix (ECM) ligands that bear laminin globular (LG) domains, occurs in several congenital/limb-girdle muscular dystrophies (also referred to as dystroglycanopathies). Recent genetic studies revealed that mutations in DAG1 (which encodes dystroglycan) and at least 17 other genes disrupt the ECM receptor function of dystroglycan and cause disease. Here, we summarize recent advances in our understanding of the enzymatic functions of two of these disease genes: the like-glycosyltransferase (LARGE) and protein O-mannose kinase (POMK, previously referred to as SGK196). In addition, we discuss the structure of the glycan that directly binds the ECM ligands and the mechanisms by which this functional motif is linked to dystroglycan. In light of the fact that dystroglycan functions as a matrix receptor and the polysaccharide synthesized by LARGE is the binding motif for matrix proteins, we propose to name this novel polysaccharide structure matriglycan.

B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I

“…49 In other studies, this glycolipid GALGT2 substrate has been shown to be a sialylpentosylceramide. 63 Although a dystroglycan is expressed as multiple glycoforms of differing molecular weights in various tissues due to its complex glycosylation pattern, 3 we identified a 300-to 350-kDa CT þ protein in WFA precipitates of GALGT2-treated muscles that is unlikely to be a dystroglycan. This protein may also contribute to the therapeutic mechanism of GALGT2.…”

“…3,4 In their most severe forms, including WWS, Fukuyama congenital MD, and muscle eye brain disease, dystroglycanopathies not only affect skeletal muscle but also eye and brain development, leading to lissencephalic changes in the cerebral cortex due to defects in the glial limitans-pial basement membrane and to ocular malformations that can include retinal detachment. 12e14 One gene that when mutated can give rise to dystroglycanopathies is fukutin-related protein, which is encoded by the FKRP gene.…”

Lassa Virus Cell Entry via Dystroglycan Involves an Unusual Pathway of Macropinocytosis

“…Initially synthesized as a single precursor polypeptide, DG core protein is processed into the Nterminal ␣-DG and the transmembrane ␤-DG (16). Binding of LASV and ECM proteins to ␣-DG critically depends on posttranslational modification by the glycosyltransferase LARGE, which adds 3-xylose-␣1,3-glucuronic acid-␤1 copolymer polysaccharides to the ␣-DG moiety in a tissue-specific manner (17)(18)(19)(20)(21)(22). A recent genome-wide haploid screen revealed that the molecular mechanisms of receptor recognition of LASV strikingly mimic those of receptor recognition of host-derived ECM proteins (23).…”

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

“…The extracellular matrix receptor function of α-DG is impaired when either DAG1 is itself mutated (limb-girdle muscular dystrophy type 2P) (10,16,17) or genes that encode putative or known glycosyltransferases that act on α-DG are mutated (Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama congenital muscular dystrophy, congenital muscular dystrophy types 1C and 1D, or limb-girdle muscular dystrophy) (12,18,19). Sarcolemmal expression of α-DG, sarcospan, and the sarcoglycan complex is reduced in patients with distinct sarcoglycan mutations (limb-girdle muscular dystrophy type 2C-F) (3)(4)(5)20).…”