A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin

Abstract

Abstract. The dystrophin-glycoprotein complex was tested for interaction with several components of the extracellular matrix as well as actin. The 156-kD dystrophin-associated glycoprotein (156-kD dystroglycan) specifically bound laminin in a calciumdependent manner and was inhibited by NaC1 (IC5o = 250 mM) but was not affected by 1,000-fold (wt/wt) excesses of lactose, IKVAV, or YIGSR peptides. Laminin binding was inhibited by heparin (IC5o = 100 /~g/ml), suggesting that one of the heparin-binding domains of laminin is involved in binding dystroglycan while negatively charged oligosaccharide moieties on dystroglycan were found to be necessary for its laminin-binding activity. No interaction between any component of the dystrophin-glycoprotein complex and fibronectin, collagen I, collagen IV, entactin, or heparan sulfate proteoglycan was detected by 125I-protein overlay and/or extracellular matrix protein-Sepharose precipitation. In addition, laminin-Sepharose quantitatively precipitated purified dystrophin-glycoprotein complex, demonstrating that the laminin-binding site is accessible when dystroglycan is associated with the complex. Dystroglycan of nonmuscle tissues also bound laminin. However, the other proteins of the striated muscle dystrophin-glycoprotein complex appear to be absent, antigenically dissimilar or less tightly associated with dystroglycan in nonmuscle tissues. Finally, we show that the dystrophin-glycoprotein complex cosediments with F-actin but does not bind calcium or calmodulin. Our results support a role for the striated muscle dystrophin-glycoprotein complex in linking the actin-based cytoskeleton with the extracellular matrix. Furthermore, our results suggest that dystrophin and dystroglycan may play substantially different functional roles in nonmuscle tissues.

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

“…7,16,19 Natively glycosylated a dystroglycan is most readily observed by binding of the IIH6 monoclonal antibody, which requires native glycosylation for binding. 59 IIH6 also can block laminin binding to the O-mannosephosphateelinked glycans present on the a dystroglycan protein.…”

Characterization of a novel Dp71 dystrophin-associated protein complex (DAPC) present in the nucleus of HeLa cells: Members of the nuclear DAPC associate with the nuclear matrix

“…In addition, an increasing number of cellular functions associated with these multiple protein complexes have been proposed, such as membrane stability, cellular signaling and force transduction [7,33,34]. The specific function of each DAPC seems to be determined by the cellular environment where it resides as well as by the unique combination of proteins that conforms the complex.…”

“…Loss of dystrophin leads to disassembly of the complex and muscle degeneration [3].It has been shown that neuronal nitric oxide synthase (nNOS) binds to skeletal muscle syntrophin through PDZ domain interactions [4]; thus, the DAPC may also regulate signal transduction. Many of the DAPC components found in skeletal muscle, including β-and ε-sarcoglycans, dystroglycans and syntrophins, are also expressed in other tissues [5][6][7][8]. Likewise, several dystrophin isoforms are ubiquitously expressed [9,10].…”

Postnatal overexpression of the CT GalNAc transferase inhibits muscular dystrophy in mdx mice without altering muscle growth or neuromuscular development: Evidence for a utrophin-independent mechanism

“…5). The amount of α dystroglycan precipitated by WGA agarose, a GlcNAc/sialic acid-binding lectin known to precipitate α dystroglycan [31,32], showed equivalent amounts of α dystroglycan were present in Galgt2-infected and mockinfected muscle lysates (Fig. 5).…”