Abstract
Cranin was described in 1987 as a membrane glycoprotein expressed in brain and many other tissues, which binds laminin with high affinity in a calcium-dependent manner. Dystrophin-associated glycoprotein ("dystroglycan") is a laminin-binding protein cloned in 1992 whose relation to cranin has remained uncertain. Here we describe the purification of cranin to homogeneity from sheep brain, show cranin to be a form of dystroglycan, and localize the N terminus of beta-dystroglycan to amino acid residue 654. We find that brain alpha-dystroglycan is tightly associated with membranes, and localizes to regions of synaptic contact as assessed by immunocytochemistry of rat cerebellum. Brain alpha-dystroglycan expresses high mannose/hybrid N-linked saccharides, terminal GalNAc residues, and the HNK-1 epitope. Although dystroglycan has previously been presumed to be a proteoglycan, the amino acid sequence, pI, O-sialoglycoprotease susceptibility, lectin-binding profile, and laminin-binding properties of brain dystroglycan are more typical of mucin-like proteins. Furthermore, using CHO mutant cell lines deficient in xylosyltransferase and galactosyltransferase I, which are required for glycosaminoglycan biosynthesis, it is shown that chondroitin sulfate and heparan sulfate are not critical for laminin binding, and indeed are apparently not expressed at all in dystroglycan from CHO cells.
Highlights
Dystroglycan appears to be important for maintaining normal muscle integrity, and it has been proposed that loss of dystroglycan from the muscle surface in DuchennelBecker and other congenital muscular dystrophies is one of the primary events leading to muscle injury in these diseases [6]
Servations that cognitive deficits and mental retardation occur in many patients with DuchennelBecker and other dystrophies [14], that matrix proteins play important roles in neuronal migration and axonal outgrowth [15], that dystrophin is enriched at postsynaptic densities in the central nervous system [16, 17], and that the gene for dystroglycan in mouse maps closely to the loci of several genetic neurological diseases [2, 13]
Since dystroglyca n is encoded by a single-copy gen e [2], and since only a single mRNA and protein sp ecies has been re ported to date [2], saccharide modifications of dystroglycan are like ly to und erl ie its tissue -specific heterogen eity
Summary
Cranin was described in 1987 as a membrane glycoprotein expressed in brain and many other tissues, which binds laminin with high affinity in a calcium-dependent manner. Dystrophin-associated glycoprotein ("dystroglycan") is a laminin-binding protein cloned in 1992 whose relation to cranin has remained uncertain.
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