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SEA domain proteolysis determines the functional composition of dystroglycan
Author(s) -
Akhavan Armin,
Crivelli Silvia N.,
Singh Manisha,
Lingappa Vishwanath R.,
Muschler John L.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-8354com
Subject(s) - dystroglycan , agrin , cleavage (geology) , microbiology and biotechnology , chemistry , proteolysis , laminin , proteostasis , transmembrane protein , transmembrane domain , biology , biochemistry , receptor , extracellular matrix , acetylcholine receptor , fracture (geology) , enzyme , paleontology
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. Akhavan, A., Crivelli, S. N., Singh, M., Lingappa, V. R., Muschler, J. L. SEA domain proteolysis determines the functional composition of dystroglycan. FASEB J. 22, 612–621 (2008)