Caveolin-3 directly interacts with the C-terminal tail of β-dystroglycan. Identification of a central WW-like domain within caveolin family members

Caveolin-3, the most recently recognized member of the caveolin gene family, is muscle-specific and is found in both cardiac and skeletal muscle, as well as smooth muscle cells. Several independent lines of evidence indicate that caveolin-3 is localized to the sarcolemma, where it associates with the dystrophin-glycoprotein complex. However, it remains unknown which component of the dystrophin complex interacts with caveolin-3. Here, we demonstrate that caveolin-3 directly interacts with β-dystroglycan, an integral membrane component of the dystrophin complex. Our results indicare that caveolin-3 co-localizes, co-fractionates, and coimmunoprecipitates with a fusion protein containing the cytoplasmic tail of β-dystroglycan. In addition, we show that a novel WW-llke domain within caveolin-3 directly recognizes the extreme C terminus of β-dystroglycan that contains a PPXY motif. As the WW domain of dystrophin recognizes the same site within β-dystroglycan, we also demonstrate that caveolin-3 can effectively block the interaction of dystrophin with β-dystroglycan. In this regard, interaction of caveolin-3 with β-dystroglycan may competitively regulate the recruitment of dystrophin to the sarcolemma. We discuss the possible implications of our findings in the context of Duchenne muscular dystrophy.