The conserved WW-domain binding sites in Dystroglycan C-terminus are essential but partially redundant for Dystroglycan function

We now find that both WW binding sites are important for maintaining full Dg function in the establishment of oocyte polarity in Drosophila. If either WW binding site is mutated, the Dg protein can still be active. However, simultaneous mutations in both WW binding sites abolish the Dg activities in both overexpression and loss-of-function oocyte polarity assays in vivo. Additionally, sequence comparisons of WW binding sites in 12 species of Drosophila, as well as in humans, reveal a high level of conservation. This preservation throughout evolution supports the idea that both WW binding sites are functionally required.Based on the obtained results we propose that the presence of the two WW binding sites in Dystroglycan secures the essential interaction between Dg and Dys and might further provide additional regulation for the cytoskeletal interactions of this complex.The Dystroglycan-Dystrophin (Dg-Dys) complex has been shown to provide cells with structural integrity by forming a conduit between the extracellular matrix and the cytoskeletal network and there are lines of evidence that implicate an additional signaling role for the complex [1,2] Dystroglycan binds to extracellular matrix components, including Laminin at its N-terminus and the actin cytoskeleton via Dystrophin at its C-terminus [3,4] Defects in these interactions can result in muscular dystrophies (MD) and various epithelial cancers [5]The characterization of the Dystrophin Glycoprotein Complex (DGC) in Drosophila has revealed that it possesses similar roles in muscle integrity and neuronal migration in flies as it does in humans [6] These abnormalities include age dependent muscle degeneration, reduced mobility, defects in eye development as manifested by altered photoreceptor axon path finding and photoreceptor morphology. Additionally, mutations in Dys and Dg affect cell polarity in Drosophila [6-8] Interestingly, some of these phenotypes are affected by the nutrition or energy metabolism in the