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Dystroglycan proteolysis is conformationally-regulated and disrupted by disease-associated mutations

Amanda N. Hayward, Wendy R. Gordon
doi: https://doi.org/10.1101/279315
Amanda N. Hayward
1Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
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Wendy R. Gordon
1Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
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  • For correspondence: wrgordon@umn.edu
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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 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.

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Posted May 15, 2018.
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Dystroglycan proteolysis is conformationally-regulated and disrupted by disease-associated mutations
Amanda N. Hayward, Wendy R. Gordon
bioRxiv 279315; doi: https://doi.org/10.1101/279315
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Dystroglycan proteolysis is conformationally-regulated and disrupted by disease-associated mutations
Amanda N. Hayward, Wendy R. Gordon
bioRxiv 279315; doi: https://doi.org/10.1101/279315

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