SEA domain proteolysis determines the functional composition of dystroglycan

Armin Akhavan, Silvia N. Crivelli, Manisha Singh, Vishwanath R. Lingappa, John Muschler

Research output: Contribution to journalArticle

37 Scopus citations

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 languageEnglish (US)
Pages (from-to)612-621
Number of pages10
JournalFASEB Journal
Volume22
Issue number2
DOIs
Publication statusPublished - Feb 2008
Externally publishedYes

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Keywords

  • Autoproteolysis
  • Laminin
  • Mucin
  • Muscular dystrophy

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

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