DYSTROGLYCAN: background.
Dystroglycan (DG) is encoded by a single gene [1-3] and is highly conserved in higher vertebrates. Recently, DG orthologues have also been identified in invertebrates [4,5]. DG is produced as a unique polipeptide chain that is successively cut in two subunits alpha and beta-DG, by a post-translational proteolitic process that would occur at the level of endoplasmatic reticulum with still unclear molecular details [6].
alpha-DG is a heavily glycosylated peripheral membrane protein which binds a number of extracellular molecules such as laminin, agrin, perlecan, neurexin and biglycan [2].
DG is expressed in a wide variety of tissues other than muscle: epithelia and the central and peripheral nervous systems [7]. The predicted molecular weight of alpha-DG core protein is about 72 kDa but when the protein is isolated from different tissues it shows size heterogeneity.
These differences are probably due to the different glycosylation fraction, which also varies even within the same cell type. alpha-DG interacts non-covalently with beta subunit, beta-DG (43kDa). beta-DG is a membrane-spanning protein whose cytoplasmic region interacts with dystrophin, its shorter isoforms, with utrophin and with other molecules that are involved in signaling transduction [12-14]. beta-DG also interacts non covalently with alpha-DG and with the sarcoglycan complex through its ectodomain [15]. DG forms a linkage between the cytoskeleton and the extracellular matrix and is crucial for the structural stability of the plasma membrane [16].
The importance of DG dramatically emerges in serious forms of muscular dystrophy (in particular Duchenne, Becker and congenital dystrophies), where the absence of DG, DG subunits and the entire DGC is frequently observed (that may depend on the abnormalities in DG targeting) in the sarcolemma. This is considered one of the major factors at molecular level leading to instability and progressive weakness of the muscle fibers and their successive necrosis.
DG also plays an essential role during the assembly of the first extra-embryonic basement membrane during mammalian morphogenesis: DG-null mouse embryos fail to develop beyond day 6.5 when the first extra-embryonic basement membrane, the Reichert's basement membrane is deposited [17].
_DYSTROGLYCAN: our contribution.
Our Research Unit has carried out a large number of studies on dystroglycan complex and on the molecular organization of its domains [18-20]. In particular, significant new insights for the knowledge at the molecular level of the two subunits interaction, alpha-DG and beta-DG, have been obtained [21-23]. Moreover, both, polyclonal and monoclonal antibodies have been already prepared starting from recombinant or synthetic peptides corresponding to specific regions of the alpha-DG protein [24].
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