Cadherin-like domains in α-dystroglycan, α/ε-sarcoglycan and yeast and bacterial proteins

Abstract

Dystrophin, a gene product that is mutated in individuals with Duchenne muscular dystrophy, is tethered to the extracellular matrix via membrane-associated multimolecular complexes. In striated muscle cells this complex contains two glycoprotein subcomplexes, the sarcoglycan (SG) and dystroglycan (DG) complexes. Disruption of these large transmembrane complexes has been shown to result in muscle disease. Altered glycosylation of α-DG is associated with two types of congenital muscular dystrophy [1. and 2.] and mutations in the α-DG–binding laminin α2 gene product is linked to a third congenital muscular dystrophy [3.]. Mutations in α-SG (adhalin) and var epsilon-SG result in type 2D limb-girdle muscular dystrophy (LGMD2D) and myoclonus-dystonia syndrome (a CNS disorder), respectively [4. and 5.]. The dystroglycan gene product is cleaved post-translationally to yield two associated glycoproteins [6.]. α-DG represents the highly glycosylated amino-terminal portion, which binds several extracellular molecules, whereas the β-DG carboxy-terminal portion spans the membrane and links to the actin cytoskeleton via dystrophin or its paralogue utrophin. DG and α/var epsilon-SG homologues are known in other vertebrates and invertebrates yet their domain contents and evolutionary heritages have not been reported. Here we reveal that DG and α/var epsilon-SG sequences contain cadherin domain homologues (see legend to Fig. 1). In animals, cadherin domain-containing proteins are adhesion molecules that modulate a wide variety of processes including cell polarization and migration [7.]. Our study also identified cadherin domains in Saccharomyces cerevisiae Axl2p (also known as Sro4p and Bud10p) and several very large proteins from magnetotactic bacteria.