Abstract
The adhesion receptor dystroglycan provides a critical mechanical link between the extracellular matrix (ECM) and the actin cytoskeleton to help muscle cells withstand contraction and neural cells maintain the blood brain barrier. Disrupting the link results in diseases such as cancer and muscular dystrophy. Proteolysis of dystroglycan by Matrix Metalloproteases (MMPs) also breaks the mechanical link and is amplified in several pathogenic states. We use a combination of biochemical, cellular and, signaling assays to show that dystroglycan proteolysis is conformationally regulated by an extracellular, juxtamembrane “proteolysis domain”, comprised of tandem Ig-like and SEA-like domains. The intact proteolysis domain is resistant to MMP cleavage, but structurally-disruptive disease-related mutations or domain truncations sensitize dystroglycan to proteolysis. Moreover, increased dystroglycan proteolysis correlates with faster cell migration, suggesting a role for abnormal proteolysis in disease pathogenesis. Finally, we find that the dystroglycan proteolysis domain can functionally substitute for the Notch proteolytic switch in the context of a Notch signaling assay, hinting at a role for mechanical force in regulating dystroglycan proteolysis.
