RT Journal Article
SR Electronic
T1 Dystroglycan proteolysis is conformationally-regulated and disrupted by disease-associated mutations
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 279315
DO 10.1101/279315
A1 Amanda N. Hayward
A1 Wendy R. Gordon
YR 2018
UL http://biorxiv.org/content/early/2018/05/15/279315.abstract
AB 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 is associated with diseases such as cancer and muscular dystrophy. Proteolysis of dystroglycan by Matrix Metalloproteases (MMPs) also breaks the mechanical anchor and is amplified in several pathogenic states. We use a combination of biochemical and cell-based 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 muscular dystrophy-related mutations sensitize dystroglycan to proteolysis. Moreover, increased dystroglycan proteolysis correlates with faster cell migration, linking proteolysis to a disease-relevant cellular phenotype. Intriguingly, previously uncharacterized cancer-associated mutations that map to the proteolysis domain similarly lead to increases in proteolysis and rates of cell migration, potentially revealing a new pathogenic mechanism in cancer.