WW and EF hand domains of dystrophin-family proteins mediate dystroglycan binding.

The membrane-spanning dystrophin glycoprotein complex mediates an indirect linkage between the actin-based cytoskeleton and the extracellular matrix. Although expressed by diverse cell types, genetic lesions of members of this complex result in muscular dystrophy phenotypes emphasizing the importance of these interactions in muscle cells. We have characterized interactions between dystrophin family members and dystroglycan: cytoskeletal and transmembrane components of the complex, respectively. Our results demonstrate that both the WW and EF hand domains of dystrophin and utrophin, an autosomal homologue of dystrophin, directly bind the cytoplasmic domain of dystroglycan. Furthermore, alpha-dystrobrevin, a more distantly related dystrophin family member which lacks a WW domain but contains the EF hand domain, binds dystroglycan. This is the first demonstration of a direct interaction between a dystrobrevin or utrophin and dystroglycan, and has implications for the organization of the dystrophin glycoprotein complex and the use of dystrophin homologues in muscular dystrophy therapy.