FORCED EXPRESSION OF DYSTROPHIN DELETION CONSTRUCTS REVEALS STRUCTURE-FUNCTION CORRELATIONS

Dystrophin plays an important role in skeletal muscle by linking the c ytoskeleton and the extracellular matrix. The amino terminus of dystro phin binds to actin and possibly other components of the subsarcolemma l cytoskeleton, while the carboxy terminus associates with a group of integral and peripheral membrane proteins and glycoproteins that are c ollectively known as the dystrophin-associated protein (DAP) complex, We have generated transgenic/mdx mice expressing ''full-length'' dystr ophin constructs, but with consecutive deletions within the COOH-termi nal domains. These mice have enabled analysis of the interaction betwe en dystrophin and members of the DAP complex and the effects that pert urbing these associations have on the dystrophic process. Deletions wi thin the cysteine-rich region disrupt the interaction between dystroph in and the DAP complex, leading to a severe dystrophic pathology. Thes e deletions remove the beta-dystroglycan-binding site, which leads to a parallel loss of both beta-dystroglycan and the sarcoglycan complex from the sarcolemma. In contrast, deletion of the alternatively splice d domain and the extreme COOH terminus has no apparent effect on the f unction of dystrophin when expressed at normal levels. The proteins re sulting from these latter two deletions supported formation of a compl etely normal DAP complex, and their expression was associated with nor mal muscle morphology in mdx mice. These data indicate that the cystei ne-rich domain is critical for functional activity, presumably by medi ating a direct interaction with beta-dystroglycan. However, the remain der of the COOH terminus is not required for assembly of the DAP compl ex.