Abstract
BackgroundDystroglycan (Dg) is a transmembrane protein that is a part of the Dystrophin Glycoprotein Complex (DGC) which connects the extracellular matrix to the actin cytoskeleton. The C-terminal end of Dg contains a number of putative SH3, SH2 and WW domain binding sites. The most C-terminal PPXY motif has been established as a binding site for Dystrophin (Dys) WW-domain. However, our previous studies indicate that both Dystroglycan PPXY motives, WWbsI and WWbsII can bind Dystrophin protein in vitro.ResultsWe 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.ConclusionBased 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.
Highlights
Dystroglycan (Dg) is a transmembrane protein that is a part of the Dystrophin Glycoprotein Complex (DGC) which connects the extracellular matrix to the actin cytoskeleton
We test whether the internal WW domain binding site is essential, whether the two WW domain binding sites are redundant or whether neither is required for Dg function in Drosophila
We generated transgenic lines expressing the following representative mutations: PPSG, which has a mismatch in WWbsII (PPSY → PPSG) and 2WW, which has mutations in both WW binding sites (WWbsI, PPPY → WAPY and WWbsII, PPSY → PPSG) (Figure 1)
Summary
Dystroglycan (Dg) is a transmembrane protein that is a part of the Dystrophin Glycoprotein Complex (DGC) which connects the extracellular matrix to the actin cytoskeleton. 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. Analogous defects observed when the Dg-Dys complex is disturbed in both flies and humans make Drosophila an attractive model for further studies on clarifying the cellular function of the DGC. In this study we dissect the roles of the two WW binding sites in the Drosophila Dystroglycan C-terminus in vivo and, interestingly, find that the sites are essential and their functions are partially overlapping
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