Abstract
Post-translational modifications of the extracellular matrix receptor dystroglycan (DG) determine its functional state, and defects in these modifications are linked to muscular dystrophies and cancers. A prominent feature of DG biosynthesis is a precursor cleavage that segregates the ligand-binding and transmembrane domains into the noncovalently attached α-and β-subunits. We investigate here the structural determinants and functional significance of this cleavage. We show that cleavage of DG elicits a conspicuous change in its ligand-binding activity. Mutations that obstruct this cleavage result in increased capacity to bind laminin, in part, due to enhanced glycosylation of α-DG. Reconstitution of DG cleavage in a cell-free expression system demonstrates that cleavage takes place in the endoplasmic reticulum, providing a suitable regulatory point for later processing events. Sequence and mutational analyses reveal that the cleavage occurs within a full SEA (sea urchin, enterokinase, agrin) module with traits matching those ascribed to autoproteolysis. Thus, cleavage of DG constitutes a control point for the modulation of its ligand-binding properties, with therapeutic implications for muscular dystrophies. We provide a structural model for the cleavage domain that is validated by experimental analysis and discuss this cleavage in the context of mucin protein and SEA domain evolution.
Original language | English (US) |
---|---|
Pages (from-to) | 612-621 |
Number of pages | 10 |
Journal | FASEB Journal |
Volume | 22 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2008 |
Externally published | Yes |
Keywords
- Autoproteolysis
- Laminin
- Mucin
- Muscular dystrophy
ASJC Scopus subject areas
- Biotechnology
- Biochemistry
- Molecular Biology
- Genetics